The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index; none of the 28 sources its claims cite is checked for support yet.
Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors
Open accessPublished version of a preprint
Abstract
Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non–small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline–based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline–based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712–21. ©2017 AACR.
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62 Own result · 18 Not checked yet · 14 Own interpretation · 2 No basis given
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In the paper
“In general, the HER2 mutant Ba/F3 cells were more sensitive to all three drugs compared to the EGFR exon 20 mutant Ba/F3 cells (Figure 1A and Figure S1).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
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“Some of these patients were enrolled in clinical trials of dacomitinib treatment, and one patient with D770delinsGY showed partial response (25).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
What the sources say
- Not checked yetcites [25] Janne, 2011, Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors, Clin Cancer Res source
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“The HER2 V777_G778insGSP mutation leads to the same changes in the HER2 protein as does the HER2 P780_Y781insGSP mutation (Table 2).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Treatment of HER2 mutant patient with afatinib
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In the paper
“Immunoblot analyses demonstrating inhibition of HER2 phosphorylation corresponded to the relative cellular sensitivities for each of the tested drugs (Figure 1D).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
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“Ba/F3 cells harboring the InsCPG were similarly sensitive to all three covalent inhibitors (Figure 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
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“Immunoblot analysis revealed higher levels of cleaved PARP in response to dacomitinib treatment than to gefitinib treatment (Figure S3C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Generation and evaluation of patient derived EGFR exon 20 cell lines
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“We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Abstract
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“Sequencing of EGFR revealed a T790M mutation in 10/12 100 nM and 5/5 1 μM treated cells.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
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“However, the glycine mutation markedly sensitized both variants to inhibition by dacomitinib (Figure 2D).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
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“In doing so, we noticed that all of the inhibitor-sensitive mutants contained a glycine in a position two residues beyond the end of the C-helix (Table 2 and Figure 2A).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
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In the paper
“EGFR mutations were detected in 678 patients (24%).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 678- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast to EGFR, only 8 different variants of HER2 exon 20 mutations were identified (Table 1).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
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In the paper
“All mutants, including WT HER2 were able to grow without IL-3 (data not shown).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plain- Asserted: passes — The authors put it forward as true.
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“In the D770_N771 insSVD mutation, the Asp770Gly mutation shifted the IC50 10-fold (p = 0.046; mean IC50 (n=3) insSVD vs. GinsSVD; t-test).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirectn = 3 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Although higher concentrations of gefitinib had some efficacy in both cell lines, afatinib and dacomitinib were substantially more effective at inhibiting cell growth as well as phosphorylation of EGFR, AKT and ERK1/2.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Generation and evaluation of patient derived EGFR exon 20 cell lines
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In the paper
“Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Based on these findings we used afatinib to treat a NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Abstract
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“The most common mutation resulted in a duplication of codon 772 to 775 (A775_G776insYVMA) and was found in 33 of 48 cases of all HER2 exon 20 insertions (68.8%).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 48- Asserted: passes — The authors put it forward as true.
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In the paper
“Routine targeted next generation sequencing of her tumor identified a HER2 V777_G778insGSP mutation (Table 2).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Treatment of HER2 mutant patient with afatinib
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In the paper
“In addition, the proliferation rates were similar with or without the glycine substitution (data not shown).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
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In the paper
“This insertion and most other insertions encoded within exon20 are not directly in contact with the ATP-site of the kinase (Figure 2A)”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
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In the paper
“The differential sensitivity of dacomitinib in the InsGY cells was mirrored by its ability to inhibit pEGFR in these cells (Figure 1B).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > EGFR exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
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In the paper
“Accordingly, we established two patient-derived cell lines (DFCI58 and DFCI127) harboring EGFR exon 20 insertion mutations (Figure S3A).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Generation and evaluation of patient derived EGFR exon 20 cell lines
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In the paper
“Eleven of 19 variants were identified in only 1 patient each.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Among the 44 EGFR exon 20 mutations, there were 19 different mutations (Table 1).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 44- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, the InsGY Ba/F3 cells were significantly more sensitive to dacomitinib (IC50 17.5 nM) than the other four exon 20 insertion Ba/F3 cell lines (p = 0.013; mean IC50 in InsGY mutant (n=4) vs. mean IC50 in other exon 20 insertion mutants; t-test).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > EGFR exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
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In the paper
“The effect in the H773_V774 insH variant was more dramatic, with an IC50 of 5 nM (figure 2D) (p < 0.001; mean IC50 (n=3) insH vs. GinsH; t-test).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirectn = 3 ·- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, by introducing a glycine into position 770 of two dacomitinib resistant EGFR exon 20 mutations, we were able to substantially enhance the efficacy of dacomitinib (Figure 2D).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
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In the paper
“Immunoblot analysis revealed HER2 phosphorylation was not completely inhibited in the resistant cells (Figure 4D).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
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In the paper
“Sequencing of HER2 from the resistant cells revealed a secondary C805S mutation in all 12 clones that was not present in the drug sensitive cells.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
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In the paper
“The findings for HER2 exon 20 mutations are similar albeit more subtle (Figure S1).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
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In the paper
“The remaining 2 drug resistant clones from the 100 nM treated group did not contain any additional EGFR mutations (data not shown).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
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In the paper
“Twelve (12) drug resistant clones were identified following selection in either 200 nM of neratinib (n=5) or 200 nM of dacomitinib (n=7).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
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In the paper
“Remarkably, by studying the drug sensitive and resistant EGFR and HER2 exon 20 insertion mutations, we uncovered a common feature among the drug sensitive mutations: the presence of a glycine at position 770 (Table 2).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
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In the paper
“In both cases described here, mutation in the covalent binding site of either EGFR (C797S) or HER2 (C805S) is sufficient to lead to drug resistance (Figure 4).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
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In the paper
“Cell proliferation assay revealed these two cell lines were resistant to all three drugs compared to parental cells (Figure 4C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“She ultimately had a clinically significant and durable response on afatinib treatment (Figure 3).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Immunoblot analysis revealed EGFR phosphorylation was not inhibited by dacomitinib in Ba/F3 cells harboring either the T790M or C797S mutations when compared to the parental InsGY cells (Figure 4B).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both T790M and C797S resulted in drug resistance to dacomitinib and afatinib (Figure 4A).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of the EGFR exon 20 mutations tested, only the IC50 value of the InsGY mutation was below this concentration (17.5nM; Figures 1A and S1), suggesting that this glycine bearing mutation may have been the reason for the unique clinical sensitivity to dacomitinib in this patient.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
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In the paper
“For EGFR, the T790M secondary mutation also results in drug resistance; to a similar degree as C797S.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“C805 is the EGFR C797 analogous cysteine residue (Figure S4).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the present study, we identify four additional rare exon 20 mutations in EGFR (InsGY) and HER2 (InsGSP, InsWLV and InsCPG) that are uniquely more sensitive to the covalent EGFR/HER2 inhibitor dacomitinib than the more common EGFR or HER2 exon 20 mutations (Figure 1A and 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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None of the sources cited for this claim have been checked yet.
In the paper
“Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Abstract
What the sources say
- Not checked yetcites [13] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol source
- Not checked yetcites [25] Janne, 2011, Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors, Clin Cancer Res source
- Not checked yetcites [26] Kris, 2015, Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors, Ann Oncol source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“In the phase I study of dacomitinib, 6 patients with EGFR exon 20 insertions were treated and 1 of 6 patients had a sustained PR (25).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [25] Janne, 2011, Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors, Clin Cancer Res source
plainn = 6- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“None of the three responders harbored the common A775_G776insYVMA HER2 mutation.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [26] Kris, 2015, Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors, Ann Oncol source
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“with the A775_G776insYVMA mutation accounting for most of the mutations seen in NSCLC (17–21).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [17] Stephens, 2004, Lung cancer: Intragenic ERBB2 kinase mutations in tumours, Nature source
- Not checked yetcites [18] Shigematsu, 2005, Somatic mutations of the HER2 kinase domain in lung adenocarcinomas, Cancer Res source
- Not checked yetcites [19] Buttitta, 2006, Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: Mutations are mainly present in adenocarcinomas with bronchioloalveolar features, Int J Cancer source
- Not checked yetcites [20] Tomizawa, 2011, Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers, Lung Cancer source
- Not checked yetcites [21] Arcila, 2012, Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas, Clin Cancer Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that inhibitor resistance may arise, at least in part, from differences in conformational dynamics of the kinase.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The insertion residues reposition Asp770, thus sterically blocking Arg776 from accessing the end of the C-helix.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As part of the switch to the inactive conformation, the side chain of Arg776 rearranges to hydrogen bond with the carbonyl group of Ala767 at the end of the C-helix (Figure 2B).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In EGFR, Asp770 and the exon 20 insertions lie at the pivot-point of the C-helix.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small molecule inhibitors.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggested that the apparent inhibition of cell growth induced by the dacomitinib treatment was mediated by enhanced apoptosis in both DFCI cell lines.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Generation and evaluation of patient derived EGFR exon 20 cell lines
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a phase II study, 3 of 26 patients with HER2 mutant NSCLC (12%) had a partial response (26).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [26] Kris, 2015, Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors, Ann Oncol source
plainn = 26- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the case of HER2, unlike EGFR, the efficacy of afatinib is more likely dependent on covalent binding than on non-covalent inhibition.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While our model linking rearrangements of Arg776 and confirmation of the C-helix to inhibitor sensitivity remains speculative, taken together, our findings show that inhibitor resistance is not an inherent feature of activating exon 20 insertions in this region.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the impact of the C805S mutation may be different than that recently described for the EGFR C797S mutation.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our studies highlight the heterogeneity among EGFR and HER2 exon 20 insertion mutations which may impact the efficacy of specific therapies.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively these findings raise the possibility that more potent and specific inhibitors of EGFR or HER2 exon 20 insertion mutations—with IC50 values closer to the Ba/F3 cell lines harboring dacomitinib sensitive mutations—may be clinically effective against a larger fraction of these cancers.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“However, there is significant clinical and biochemical heterogeneity among EGFR or HER2 exon 20 mutations.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
What the sources say
- Not checked yetcites [8] Yasuda, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci Transl Med source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Mutations in C797 (to C797S) have recently been demonstrated to lead to resistance to mutant selective EGFR inhibitors both in vitro (WZ4002, rociletinib, osimertinib) and in lung cancer patients (31, 33).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
What the sources say
- Not checked yetcites [31] Ercan, 2015, EGFR mutations and resistance to irreversible pyrimidine based EGFR inhibitors, Clin Cancer Res source
- Not checked yetcites [33] Thress, 2015, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, Nat Med source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
In the paper
“In the phase II trial of dacomitinib, the mean trough concentration following dosing with 45mg of dacomitinib once daily was 56.7–74.7ng/mL (approximately 120–160nmol/L) (24).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
What the sources say
- Not checked yetcites [24] Janne, 2014, Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial, Lancet Oncol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of the EGFR exon 20 mutations tested, only the IC50 value of the InsGY mutation was below this concentration (17.5nM; Figures 1A and S1), suggesting that this glycine bearing mutation may have been the reason for the unique clinical sensitivity to dacomitinib in this patient.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 29
- The quote only partly states this claim. 2
- Probably not a substantial claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These cells were more sensitive to neratinib although not as sensitive as those the WT HER2 cells (Figure 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both mutants led to transformation and IL-3 independent growth (data not shown).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DFCI58 was established from the adenocarcinoma of a 60-year-old male. He was diagnosed with stage IV disease and and an EGFR H773_V774insNPH exon 20 mutation was identified.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Generation and evaluation of patient derived EGFR exon 20 cell lines
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The InsGY Ba/F3 cells were also slightly more sensitive to afatinib while all five exon 20 insertion mutations were relatively more resistant to neratinib.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > EGFR exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The response was sustained for 7 months with eventual clinical progression due to leptomeningeal carcinomatosis.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Treatment of HER2 mutant patient with afatinib
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Forty four EGFR mutations were insertion mutations in exon 20 (7% of EGFR mutant cases and 1.7% of all tested cases).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 44- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, contrary to our hypothesis, these substitutions did not uniformly confer resistance; the alanine mutant was slightly more resistant while the arginine and aspartic acid mutants exhibited increased sensitivity (Figure 2D).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While this position is accessible in wild type EGFR, it is blocked by Asp770 in the insertion mutant (Figure 2C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The InsYVMA Ba/F3 cells were the most resistant with IC50 values higher than that seen for WT HER2 (Figure 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Between 2004 and 2015, 2789 patients were tested for EGFR mutations and between 2009 and 2015, 1901 patients were tested for HER2 mutations.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 2,789- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All of the EGFR exon 20 insertion containing Ba/F3 cells were resistant to gefitinib while the EGFR WT cells remained sensitive (data not shown).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > EGFR exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Some HER2 exon 20 patients were also enrolled into clinical trials of dacomitinib, and two patients with a P780_Y781insGSP and one patient with a M774delinsWLV achieved a partial response (26).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
What the sources say
- Not checked yetcites [26] Kris, 2015, Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors, Ann Oncol source
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DFCI127 was established from the adenocarcinoma of a 42-year-old female. She was diagnosed with stage IV disease and had an EGFR P772_H773insPNP exon 20 mutation.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Generation and evaluation of patient derived EGFR exon 20 cell lines
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Five of the 8 variants were detected only once.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“She experienced significant tumor shrinkage (Figure 3), accompanied by a decrease in the requirement for supplemental oxygen.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Treatment of HER2 mutant patient with afatinib
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All exon 20 EGFR mutant Ba/F3 cells were able to grow without interleukin-3 (IL-3) with the exception of EGFR WT Ba/F3 cells which required 10 ng/ml of EGF to sustain growth (data not shown).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > EGFR exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar to the Ba/F3 cells, neratinib was most effective at inhibiting the growth of the InsGSP and InsYVMA colonies while dacomitinib was most effective against the InsWLV cells (Figures S2A and S2B).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Dacomitinib was a more potent inhibitor of WT EGFR Ba/F3 cells (Figure 1A and Figure S1).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > EGFR exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most common one was a duplication of codon 768 to 770 resulting in D770_N771insSVD. The second most common one was a duplication of codon 767 to 769 resulting in V769_D770insASV. These two insertions are very similar in their locations and together accounted for 36.3% (16 in 44 cases) of all EGFR exon 20 insertions.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 44- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Seventeen (17) drug resistant clones were expanded and identified to be drug resistant; 12 from the 100 nM and 5 from the 1 μM treated cells.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Forty seven HER2 mutations were detected in exon 20 (2.5% of all tested cases).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
plainn = 1,901- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Three of these mutations were initially identified from the tumors of lung cancer patients who had clinically responded to dacomitinib while the fourth was identified as an in vitro mutation conferring drug sensitivity (Figure 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The HER2 mutations identified from dacomitinib responding patients were also the most sensitive to dacomitinib in vitro (Figure 1C) but the differences in the IC50 values between these and mutations from patients with no response (such as HER2 InsYVMA) were not as pronounced as in those with the EGFR exon 20 mutations (Figure 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A review of 84 patients with exon 20 insertions across different series treated with either gefitinib or erlotinib demonstrated a RR of only 11% with a PFS of 2.4 months (12).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [12] Naidoo, 2015, Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib, Cancer source
boostedn = 84- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Similarly, treatment with afatinib in this patient population is also associated with a low RR and PFS (8.7% and 2.7 months, respectively) (13).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [13] Yang, 2015, Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: A combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, Lancet Oncol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutations in HER2 are oncogenic both in vitro and in vivo (14–16).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [14] Shimamura, 2006, Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272, Cancer Res source
- Not checked yetcites [15] Wang, 2006, HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors, Cancer Cell source
- Not checked yetcites [16] Perera, 2009, HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy, Proc Natl Acad Sci U S A source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This approach has previously led to identification of clinically relevant drug resistance mutations to EGFR TKIs (30, 31).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Identification of mutations that cause drug resistance in drug sensitive EGFR or HER2 exon 20 mutant cells
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Only one crystal structure is available for an exon 20 variant (the insNPG mutant) and it reveals an inhibitor binding site that is essentially indistinguishable from that of the inhibitor-sensitive L858R mutant (8).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Structural insights into inhibitor sensitivity of exon20 insertion mutants
What the sources say
- Not checked yetcites [8] Yasuda, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci Transl Med source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“While none of the patients treated with neratinib alone responded (RR: 0%), 3 of 14 (RR: 21%) patients treated with the combination of neratinib/temsirolimus had a PR (23).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Introduction
What the sources say
- Not checked yetcites [23] Besse, 2014, Neratinib (N) with or without temsirolimus (TEM) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: an international randomized phase II study, Ann Oncol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Although the vast majority are associated with resistance to EGFR inhibitors, previous studies have identified a unique EGFR exon 20 mutation (A763_Y764insFQEA) that remained sensitive to erlotinib (8).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
What the sources say
- Not checked yetcites [8] Yasuda, 2013, Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer, Sci Transl Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, glycine mutations can restore inhibitor sensitivity without abrogating transforming activity.”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Cells expressing an EGFR activating mutation and C797S in the absence of T790M are resistant to mutant selective EGFR inhibitors (WZ4002, osimertinib and rociletinib) but remain sensitive to afatinib (31).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Discussion
What the sources say
- Not checked yetcites [31] Ercan, 2015, EGFR mutations and resistance to irreversible pyrimidine based EGFR inhibitors, Clin Cancer Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
The paper relies on this without support.
EGFR exon 20 insertion mutations and HER2 exon 20 insertion mutations occur at structurally analogous positions.
“Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20.”
“Notably, EGFR exon 20 insertion mutations occur in a structurally analogous position as exon 20 insertion mutations in HER2.”
The paper relies on this without support.
EGFR C797 is the covalent binding site for neratinib, dacomitinib, and afatinib.
“EGFR C797 is the site of covalent binding of neratinib, dacomitinib and afatinib.”
The paper relies on this without support.
There are currently no effective or approved targeted therapies for patients with EGFR or HER2 exon 20 mutant lung tumors.
“Lung cancer patients harboring EGFR or HER2 exon 20 mutant tumors represent a unique subset of patients for whom there are currently no effective or approved targeted therapies.”
The paper relies on this without support.
No features among EGFR or HER2 exon 20 mutations have been identified that predict clinical sensitivity to existing covalent EGFR/HER2 inhibitors.
“To date, no features among the different EGFR or HER2 exon 20 mutations have been identified that could predict clinical sensitivity to existing covalent EGFR or HER2 inhibitors.”
The paper relies on this without support.
The common EGFR exon 20 mutations InsSVD and InsASV account for about one-third of all exon 20 mutations, and HER2 InsYVMA accounts for about two-thirds of HER2 exon 20 mutations.
“Furthermore, there continues to be a need to develop effective therapies for patients with the more common EGFR exon 20 mutation (InsSVD and InsASV, accounting for ~ 1/3 of all exon 20 mutations) and HER2 exon 20 mutations (InsYVMA, accounting for ~ 2/3 of all exon 20 mutations).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7–10.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [10]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn the citing paper
“Patients with atypical EGFR mutations show heterogeneous and reduced responses to EGFR inhibitors1,3,7–10, including osimertinib12.”
From Structure-based classification predicts drug response in EGFR-mutant NSCLC (2021) · cites this paper as [10]
In the citing paper
“In a recent study of rare EGFR and HER2 exon 20 mutations, the authors found a heterogeneous response to covalent quinazoline-based second-generation inhibitors, such as dacomitinib and afatinib; however, the concentrations that were required to target more common exon 20 insertion mutations were above what are clinically achievable24.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
“Forty seven HER2 mutations were detected in exon 20 (2.5% of all tested cases).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
“The most common mutation resulted in a duplication of codon 772 to 775 (A775_G776insYVMA) and was found in 33 of 48 cases of all HER2 exon 20 insertions (68.8%).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“Forty four EGFR mutations were insertion mutations in exon 20 (7% of EGFR mutant cases and 1.7% of all tested cases).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > Spectrum of EGFR and HER2 mutations in NSCLC patients
Reported 1.7 · recomputed 1.577626
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
“We evaluated the efficacy of neratinib, dacomitinib and afatinib in all six HER2 exon 20 insertion mutant Ba/F3 cell lines (Figure 1C).”
§ Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors > Results > HER2 exon 20 insertions and sensitivity to quinazoline based EGFR inhibitors
“We also generated and studied WT and 5 different HER2 exon 20 insertion Ba/F3 cell lines.”
Citations
Cites
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525
Zhou, C., Wu, Y.-L., Chen, G., Feng, J., Liu, X.-Q., Wang, C., Zhang, S., Wang, J., Zhou, S., Ren, S., et al. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70184-x · Cited by 4,081
Crizotinib versus Chemotherapy in Advanced ALK -Positive Lung Cancer
Shaw, A. T., Kim, D.-W., Nakagawa, K., Seto, T., Crinó, L., Ahn, M.-J., De Pas, T., Besse, B., Solomon, B. J., Blackhall, F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1214886 · Cited by 3,381
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C., Majem, M., Lopez-Vivanco, G., Isla, D., Provencio, M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0904554 · Cited by 2,373
Thress, K. S., Paweletz, C. P., Felip, E., Cho, B. C., Stetson, D., Dougherty, B., Lai, Z., Markovets, A., Vivancos, A., Kuang, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3854 · Cited by 1,589
Self-citationNovel mutant-selective EGFR kinase inhibitors against EGFR T790M
Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., et al. (2009) · Nature · doi:10.1038/nature08622 · Cited by 1,013
Self-citationYang, J. C.-H., Sequist, L. V., Geater, S. L., Tsai, C.-M., Mok, T. S. K., Schuler, M., Yamamoto, N., Yu, C.-J., Ou, S.-H. I., Zhou, C., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00026-1 · Cited by 1,002
Intragenic ERBB2 kinase mutations in tumours
Stephens, P., Hunter, C., Bignell, G., Edkins, S., Davies, H., Teague, J., Stevens, C., O'Meara, S., Smith, R., Parker, A., et al. (2004) · Nature · doi:10.1038/431525b · Cited by 802
Awad, M. M., Oxnard, G. R., Jackman, D. M., Savukoski, D. O., Hall, D., Shivdasani, P., Heng, J. C., Dahlberg, S. E., Janne, P. A., Verma, S., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.63.4600 · Cited by 714
Self-citation
Cited by
Sorted by citations
Planchard, D., Popat, S., Kerr, K., Novello, S., Smit, E. F., Faivre-Finn, C., Mok, T. S., Reck, M., Van Schil, P. E., Hellmann, M. D., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy275 · Cited by 2,274
Understanding and targeting resistance mechanisms in NSCLC
Rotow, J. K., & Bivona, T. G. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.84 · Cited by 997
HER kinase inhibition in patients with HER2- and HER3-mutant cancers
Hyman, D. M., Piha-Paul, S. A., Won, H., Rodon, J., Saura, C., Shapiro, G. I., Juric, D., Quinn, D. I., Moreno, V., Doger, B., et al. (2018) · Nature · doi:10.1038/nature25475 · Cited by 780
Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors
Westover, D., Zugazagoitia, J., Cho, B. C., Lovly, C. M., & Paz-Ares, L. (2018) · Annals of Oncology · doi:10.1093/annonc/mdx703 · Cited by 766
Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer
Harrison, P. T., Vyse, S., & Huang, P. H. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.09.015 · Cited by 637
Metadata
- Authors
- Kosaka, T., Tanizaki, J., Paranal, R. M., Endoh, H., Lydon, C., Capelletti, M., Repellin, C. E., Choi, J., Ogino, A., Calles, A., Ercan, D., Redig, A. J., Bahcall, M., Oxnard, G. R., Eck, M. J., & Jänne, P. A.
- Affiliations
- Harvard University (US)
- 1Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.
- ORCID
- Venue
- Cancer Research
- Published
- 2017-05-14
- Volume
- 77
- Issue
- 10
- Pages
- 2712-2721
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5596996
- OpenAlex
- W2598622710
- Cited by
- 131
- References
- 33
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 18 · 2022: 17 · 2021: 22 · 2020: 12 · 2019: 16 · 2018: 23 · 2017: 7
- FWCI
- 13.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (R01CA135257, R01CA114465)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- EGFR exon 20 insertion, HER2 exon 20 insertion, non-small cell lung cancer, dacomitinib, afatinib, acquired drug resistance, T790M, C797S, structural modeling, drug sensitivity
- MeSH terms
- Adult, Animals, Antineoplastic Agents, Codon, Disease Models, Animal, Dose-Response Relationship, Drug, Exons, Female, Humans, Lung Neoplasms, Male, Middle Aged, Models, Molecular, Molecular Conformation, Protein Binding, Tomography, X-Ray Computed, Gene Expression, Mutagenesis, Insertional, Treatment Outcome, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Amino Acid Substitution, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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