The DOI matches its Crossref record; 38 of the 40 references it cites were found in a registry or an index, and 2 are not checked yet; none of the 55 sources its claims cite is checked for support yet.
EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors
Open accessPublished version of a preprint
Abstract
Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents. Experimental Design: We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR-mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug-resistant EGFR mutations. Results: We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR-sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization. Conclusions: Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR. Clin Cancer Res; 21(17); 3913–23. ©2015 AACR. See related commentary by Ayeni et al., p. 3818
Checked 2026-10-06 · 2 references not checked yet
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58 Own result · 27 Not checked yet · 9 Own interpretation · 5 Own method
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In the paper
“In the triple mutants (EGFR activating mutation/T790M with L718Q or L844V), none of the quinazoline based EGFR inhibitors tested showed any efficacy (Figure 2D, S4A and S4B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Afatinib was a substantially better inhibitor of WT EGFR; AZD9291 inhibited WT EGFR at lower concentrations than WZ4002 or CO-1686 (Figure 3A).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Differential efficacy of clinical mutant selective EGFR inhibitors in models harboring EGFR mutations
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In the paper
“expression of either L718Q or L844V containing constructs resulted in resistance to WZ4002, CO-1686 and afatinib (Figure 5A).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR tertiary mutations cause resistance in endogenous EGFR mutant lung cancer models
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, the combination was very effective in Ba/F3 cells harboring L858R or Del E746_A750 in conjunction with either L718Q or L844V (Figure 2G and S4D).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We were not able to identify any secondary mutations using the Del E746_A750 Ba/F3 cells using our ENU mutagenesis assay (Figure 1A and Table S1).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
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In the paper
“Afatinib was most effective in models harboring an EGFR activating mutation (L858R or Del 19) along with either the L718Q or L844V mutations (Figure 4A and B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Efficacy of clinical irreversible EGFR inhibitors on models harboring EGFR tertiary mutations
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“Three mutations, L718Q (codon 2153, T>A), L844V (codon 2530, C>G) and C797S (codon 2389, T>A) were identified with different frequencies in the 4 different Ba/F3 cell lines (Figures 1A and S1 and Table S1).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
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“In support of this, in the presence of the L718Q mutation, basal EGFR phosphorylation was reduced in EGFR Del E746_A750 cells (Figure S2).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
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In the paper
“Neither EGFR L718Q nor L844V mutations were sufficient to lead to IL-3 independent cell growth in the background of wild type (WT) EGFR when introduced into Ba/F3 cells (Figure 1B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
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In the paper
“None of the drugs were effective in triple-mutant models harboring C797S or the EGFR exon 20 insertion mutation A768_V769dupASV (Table S3).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Differential efficacy of clinical mutant selective EGFR inhibitors in models harboring EGFR mutations
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“While afatinib/cetuximab had some effect on cell growth (Figure 5C) and EGFR signaling (Figure 5D) in cells expressing L718Q or L844V, in neither model was the effect as robust as observed with AZD9291 (Figure 5C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR tertiary mutations cause resistance in endogenous EGFR mutant lung cancer models
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In the paper
“Treatment with cetuximab disrupted dimerization, which resulted in inhibition of EGFR phosphorylation and growth inhibition of the cells (Figure 6D and 6E).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Existing EGFR inhibitors are effective in some genomic contexts containing EGFR C797S
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Of the pyrimidine inhibitors, only AZD9291 inhibited Del/L718Q, Del/L844V and L858R/L844V cells, but was less effective against the L858R/L718Q cells (Figure 4A).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Efficacy of clinical irreversible EGFR inhibitors on models harboring EGFR tertiary mutations
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In the paper
“In the triple mutant Ba/F3 cells, only AZD9291 was effective in models harboring L844V while having a minimal effect against those with the L718Q mutation (Figure 4A).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Efficacy of clinical irreversible EGFR inhibitors on models harboring EGFR tertiary mutations
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“While multiple EGFR mutations were recovered at 100 nM for both WZ4002 and CO-1686, > 90% of the clones recovered using AZD9291 harbored a mutation in C797 mutation (Figure 4D and Table S4).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Efficacy of clinical irreversible EGFR inhibitors on models harboring EGFR tertiary mutations
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, while PC9 cells (EGFR E746_A750) expressing EGFR DelE746_A750/C797S were resistant to WZ4002, CO-1686 and AZD9291, they remained sensitive to both afatinib and gefitinib (Figure 6A and 6B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Existing EGFR inhibitors are effective in some genomic contexts containing EGFR C797S
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“At 1 μM, only clones containing mutations in C797 (either C797S or C797G) were recovered for both WZ4002 and AZD9291 while roughly equal numbers of L718Q and C797S clones were recovered with CO-1686 (Figure 4D).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Efficacy of clinical irreversible EGFR inhibitors on models harboring EGFR tertiary mutations
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > Abstract > Results
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In the paper
“While L858R/T790M/L718Q and L858R/T790M/L844V existed predominately as monomers, the L858R/T790M/C797S was present in both monomers and dimers (Figure 6D).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Existing EGFR inhibitors are effective in some genomic contexts containing EGFR C797S
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, in the background of an EGFR activating mutation alone, afatinib and CL-387,785, were particularly effective at inhibiting the growth of either L718Q or L844V containing cells which was mirrored by inhibition of EGFR phosphorylation (Figure 2E and S4C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Gefitinib, a reversible quinazoline EGFR inhibitor, was moderately effective, with greater efficacy in the L844V model (Figure 1C and Table S2).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
plaindirect- 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
“Analogously, phosphorylation of EGFR and downstream signaling pathways were inhibited by AZD9291 but not WZ4002 or CO-1686 in PC9 GR cells expressing either EGFR del E746_A750/T790M/L718Q or EGFR del E746_A750/T790M/L844V (Figure 5B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR tertiary mutations cause resistance in endogenous EGFR mutant lung cancer models
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Unlike the L858R counterpart, Del 19/T790M/C797S exists predominately as a monomer with no effect on EGFR phosphorylation of cell growth following cetuximab treatment (Figure S7A and S7B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Existing EGFR inhibitors are effective in some genomic contexts containing EGFR C797S
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“With gefitinib we only recovered EGFR T790M containing clones while with WZ4002 only L718Q containing clones were recovered (Figure 2F).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Engineered EGFR Del E746_A750/L718Q but not EGFR L858R/L718Q Ba/F3 cells demonstrated a growth disadvantage providing one explanation as to why these were not recovered in our original assay (Figure 1D).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“Cells containing the Q791R (codon 2372, A>G) mutation were relatively resistant to W4002 and CO-1686 but remained sensitive to AZD9291 and afatinib (Figure S5A–D).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Efficacy of clinical irreversible EGFR inhibitors on models harboring EGFR tertiary mutations
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“EGFR L718Q, L844V and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > Abstract > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TX2-30 labeled the mutant EGFR proteins more efficiently than WT, consistent with the ‘mutant’ selectivity exhibited by the parental WZ4002 compound (Figure 2C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AZD9291 retains activity against L844V and moderate activity in models harboring EGFR L718Q, although only in the background on an EGFR exon 19 deletion, while both mutations mediate resistance to CO-1686 (Figures 4A, 4C and 5A).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > DISCUSSION
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In the paper
“Alternatively, combinations of mutant selective and quinazoline based EGFR inhibitors could be used together as initial treatment for EGFR mutant NSCLC, as the two classes of EGFR inhibitors are effective against non-cross resistant mutations and together prevent the emergence of resistant clones (Figures 2F and 5C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These mutations are not oncogenic but mediate drug resistance likely through steric hindrance and impact drug binding (Figure 2A–C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We also identify secondary mutations in EGFR, L718Q and L844V, both of which occur more frequently in WZ4002 and CO-1686 resistant models (Figure 4D).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation in EGFR at position T790 (T790M)(10).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > INTRODUCTION
What the sources say
- Not checked yetcites [10] Yu, 2013, Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers, Clin Cancer Res source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, in lung cancer patients, afatinib is only effective in EGFR TKI naive EGFR mutant cancers and has a RR of < 10% in patients with NSCLC that have developed resistance to gefitinib or erlotinib (13).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > INTRODUCTION
What the sources say
- Not checked yetcites [13] Miller, 2012, Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial, Lancet Oncol source
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In the paper
“Prior studies have demonstrated that some EGFR mutant proteins, including L858R/T790M, do not require dimerization for oncogenic transformation (35).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Existing EGFR inhibitors are effective in some genomic contexts containing EGFR C797S
What the sources say
- Not checked yetcites [35] Janjigian, 2014, Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations, Cancer Discov source
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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
“The L718Q substitution likely sterically interferes with binding of the compound, while the L844V mutation can be expected to remove favorable contacts with the inhibitor (Figure 2B).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“All constructs were confirmed by DNA sequencing.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > MATERIALS AND METHODS > Generation of Drug-Resistant Cells Lines
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“All experimental points were set up in three wells and all experiments were repeated at least twice.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > MATERIALS AND METHODS > Cell proliferation assays and Growth Assays
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, other mutants, including EGFR L858R, require dimerization and are sensitive to the anti-EGFR antibody cetuximab which disrupts EGFR dimerization (35).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Existing EGFR inhibitors are effective in some genomic contexts containing EGFR C797S
What the sources say
- Not checked yetcites [35] Janjigian, 2014, Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations, Cancer Discov 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.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Examination of the crystal structure of WZ4002 in complex with EGFR T790M (14) reveals that both L718 and L844 are in direct contact with the inhibitor; L718 primarily with the aniline ring and L844 with the pyrimidine ring (Figure 2A).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
What the sources say
- Not checked yetcites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature 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
“They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (14–16).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > INTRODUCTION
What the sources say
- Not checked yetcites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source
- Not checked yetcites [15] Walter, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov source
- Not checked yetcites [16] Cross, 2014, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov source
hedgeddirect- 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
“C797 is the site of covalent binding of WZ4002 and previously demonstrated to lead to drug resistance if mutated to serine (14).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
What the sources say
- Not checked yetcites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature 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.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All cell lines were authenticated in September 2014 using the Promega Geneprint 16 cell ID system and was performed at the Research Technology Support Facility at Michigan State University.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > MATERIALS AND METHODS > Cell Culture and Reagents
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The experiment was repeated three independent times.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > MATERIALS AND METHODS > Cell proliferation assays and Growth Assays
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. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experimental points were set up in six wells and all experiments were repeated at least three times.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > MATERIALS AND METHODS > Cell proliferation assays and Growth Assays
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. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutations at L718 resulting in L718P, L718V and L718M mutations have been described but not EGFR L718Q (28–31).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
What the sources say
- Not checked yetcites [28] Penzel, 2011, EGFR mutation detection in NSCLC–assessment of diagnostic application and recommendations of the German Panel for Mutation Testing in NSCLC, Virchows Arch source
- Not checked yetcites [29] Locatelli-Sanchez, 2013, Routine EGFR molecular analysis in non-small-cell lung cancer patients is feasible: exons 18–21 sequencing results of 753 patients and subsequent clinical outcomes, Lung source
- Not checked yetcites [30] Liu, 2013, Screening for EGFR and KRAS mutations in non-small cell lung carcinomas using DNA extraction by hydrothermal pressure coupled with PCR-based direct sequencing, Int J Clin Exp Pathol
- Not checked yetcites [31] Munfus-McCray, 2013, Comparison of EGFR and KRAS mutations in primary and unpaired metastatic lung adenocarcinoma with potential chemotherapy effect, Human Pathol source
plain- 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.
In the paper
“The L844V mutation has been previously observed in a NSCLC patient (27).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > Identification of novel drug resistant mutations
What the sources say
- Not checked yetcites [27] Zhou, 2010, A structure-guided approach to creating covalent FGFR inhibitors, Chem Biol source
plainSingle case- 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 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, in the presence of either the L718Q or the L844V mutation, we recovered less WT and mutant EGFR suggesting that these mutations impact drug binding (Figure 2C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > RESULTS > EGFR L718Q and L844V impact WZ4002 binding and retain sensitivity to quinazoline based EGFR inhibitors
hedgeddirect- 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
“CO-1686 is structurally more closely related to WZ4002 than to AZD9291 and in all of the models tested CO-1686 is very similar in vitro to WZ4002 (14–16).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > DISCUSSION
What the sources say
- Not checked yetcites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source
- Not checked yetcites [15] Walter, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov source
- Not checked yetcites [16] Cross, 2014, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov 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
“Given the increased ATP affinity imparted by the T790M, it may not be possible to identify a non-covalent EGFR inhibitor with sufficient affinity to inhibit EGFR in the presence mutations in C797 and hence an alternative approach may be necessary.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR 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.
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
“These mutations are not oncogenic but mediate drug resistance likely through steric hindrance and impact drug binding (Figure 2A–C).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR 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.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Additional pre-clinical studies have also identified activation of MAPK signaling and IGF1R signaling as well as epithelial to mesenchymal (EMT) transition as potential resistance mechanisms to WZ4002 and CO-1686 (15, 19, 20).”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR inhibitors > DISCUSSION
What the sources say
- Not checked yetcites [15] Walter, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov source
- Not checked yetcites [19] Ercan, 2012, Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors, Cancer Discov source
- Not checked yetcites [20] Cortot, 2013, Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway, Cancer Res source
hedgedconditional- 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 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
“This has immediate clinical implications as gefitinib and afatinib are approved EGFR inhibitors and could be clinically effective in EGFR mutant EGFR TKI naive patients who develop these drug resistance mutations following initial treatment with either AZD9291 or CO-1686.”
§ EGFR mutations and resistance to Irreversible pyrimidine based EGFR 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.
It may state two separate claims as one.
- The authors state this as an assumption: The tertiary mutations L718Q, L844V, and C797S will also arise in patients treated with CO-1686 and AZD9291.
The paper relies on this without support.
Most patients treated with an EGFR TKI will eventually develop disease progression.
“However, the vast majority of patients will develop disease progression following successful treatment with an EGFR TKI.”
The paper relies on this without support.
Afatinib's inhibition of wild-type EGFR causes toxicities that prevent dose escalation to levels needed to inhibit T790M.
“Afatinib is a potent inhibitor of both mutant and wild type (WT) EGFR. Inhibition of WT EGFR leads to toxicities, including skin rash and diarrhea, which limits the ability to escalate afatinib doses in patients to those necessary to inhibit EGFR T790M.”
The paper relies on this without support.
Secondary mutations in EGFR itself have not been described as a mechanism of acquired resistance.
“Secondary mutations in EGFR itself have not been described as a mechanism of acquired resistance.”
The paper relies on this without support.
Ba/F3 cell models with EGFR mutations are predictive of acquired resistance mechanisms that occur in human lung cancer.
“Understanding the mechanism (s) of resistance to this class of agents may both help predict the mechanism(s) that will occur in patients and allow the development of subsequent treatment strategies.”
The authors state this as an assumption.
The tertiary mutations L718Q, L844V, and C797S will also arise in patients treated with CO-1686 and AZD9291.
“assuming these tertiary mutations will also arise in patients treated with CO-1686 and AZD9291.”
The paper relies on this without support.
Acquired drug resistance limits the long-term clinical success of targeted therapies including EGFR inhibitors in patients with EGFR mutant NSCLC.
“Acquired drug resistance limits the long term clinical success of targeted therapies including EGFR inhibitors in patients with EGFR mutant NSCLC.”
The paper relies on this without support.
Acquired resistance will also develop to mutant-selective EGFR inhibitors including WZ4002, CO-1686, and AZD9291.
“However, it is fully anticipated that acquired resistance will also develop to this class of EGFR inhibitors.”
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?
In the citing paper
“This approach has previously led to identification of clinically relevant drug resistance mutations to EGFR TKIs (30, 31).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [31]
In the citing 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).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [31]
In the citing 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).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [31]
In the citing paper
“In the T790M-preserved group, previously defined osimertinib-resistant EGFR mutations (11/19; C797S: 8; C797G: 1; L792H: 2 [20] [21]) were the most common resistance mechanisms.”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC (2018) · cites this paper as [20]
In the citing paper
“However, in vitro work has also demonstrated that L718Q may still respond to first- and second-generation of EGFR inhibitors, especially when T790M is lost, as is the case for the patient No. 29[20].”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC (2018) · cites this paper as [20]
Citations
Cites
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Metadata
- Authors
- Ercan, D., Choi, H. G., Yun, C.-H., Capelletti, M., Xie, T., Eck, M. J., Gray, N. S., & Jänne, P. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- 1Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
- Corresponding author
- Gray, Nathanael S.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-08-31
- Volume
- 21
- Issue
- 17
- Pages
- 3913-3923
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4791951
- OpenAlex
- W2126709309
- Cited by
- 368
- References
- 40
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 19 · 2023: 18 · 2022: 37 · 2021: 35 · 2020: 35 · 2019: 36 · 2018: 54 · 2017: 47 · 2016: 49 · 2015: 10
- FWCI
- 42.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA114465, R01CA135257, P01CA154303)
- 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 mutation, acquired drug resistance, T790M mutation, EGFR C797S, L858R mutation, WZ4002, osimertinib, gefitinib, erlotinib, afatinib, cetuximab, EGFR dimerization, lung cancer, Ba/F3 cells
- MeSH terms
- Afatinib, Acrylamides, Animals, Codon, Humans, Models, Molecular, Molecular Conformation, Mutation, Pyrimidines, Quinazolines, Drug Resistance, Neoplasm, Amino Acid Substitution, Inhibitory Concentration 50, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, 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).
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