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Cited by 381Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors

Open access
Ercan, Dalia, Choi, Hwan Geun, Yun, Cai-Hong, Capelletti, Marzia, Xie, Ting, Eck, Michael J., Gray, Nathanael S., Jänne, Pasi A.·2015·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-14-2789PMC PMC4791951

Published version of a preprint

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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

Verified 2026-10-06 · 2 references not checked yet

Integrity signals

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Crossref · 10.1158/1078-0432.ccr-14-2789

Cites

38 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 55 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In triple mutants with an EGFR activating mutation, T790M, and either L718Q or L844V, none of the tested quinazoline EGFR inhibitors showed efficacy.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    Afatinib was a substantially better inhibitor of wild-type EGFR than the other drugs.

    “Afatinib was a substantially better inhibitor of WT EGFR; AZD9291 inhibited WT EGFR at lower concentrations than WZ4002 or CO-1686 (Figure 3A).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Expression of EGFR del E746_A750/T790M/L718Q or L844V in NSCLC cell lines (PC9GR4 or HCC827 EPR) caused resistance to WZ4002, CO-1686, and afatinib.

    “expression of either L718Q or L844V containing constructs resulted in resistance to WZ4002, CO-1686 and afatinib (Figure 5A).”
    Quote in the paperSubstantial claim
  • Findingown data

    The combination of gefitinib and WZ4002 was very effective in Ba/F3 cells carrying L858R or Del E746_A750 together with L718Q or L844V.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    No secondary mutations were identified in Del E746_A750 Ba/F3 cells using the ENU mutagenesis assay.

    “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).”
    Quote in the paperSubstantial claim
  • May combine two claims. 36
  • The quote only partly states this claim. 3
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    Afatinib plus cetuximab had some effect on cell growth and EGFR signaling in PC9 GR cells expressing L718Q or L844V, but the effect was less robust than AZD9291 in both models.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cetuximab treatment disrupted dimerization and resulted in inhibition of EGFR phosphorylation and growth inhibition of the cells.

    “Treatment with cetuximab disrupted dimerization, which resulted in inhibition of EGFR phosphorylation and growth inhibition of the cells (Figure 6D and 6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among the pyrimidine inhibitors, only AZD9291 inhibited Del/L718Q, Del/L844V, and L858R/L844V cells, but it was less effective against L858R/L718Q cells.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In triple-mutant Ba/F3 cells, only AZD9291 was effective in L844V models and had minimal effect against L718Q models.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 100 nM, multiple EGFR mutations were recovered with WZ4002 and CO-1686, while more than 90% of clones recovered with AZD9291 had a C797 mutation.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PC9 cells expressing EGFR DelE746_A750/C797S were resistant to WZ4002, CO-1686, and AZD9291 but remained sensitive to afatinib and gefitinib.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 1 μM, only C797 mutations, either C797S or C797G, were recovered with WZ4002 and AZD9291, while roughly equal numbers of L718Q and C797S clones were recovered with CO-1686.

    “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).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    C797S together with Del 19 or L858R and T790M causes resistance to all current EGFR inhibitors.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In transformed Ba/F3 cells, L858R/T790M/L718Q and L858R/T790M/L844V existed predominantly as monomers, whereas L858R/T790M/C797S was present as both monomers and dimers.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With an EGFR activating mutation alone, afatinib and CL-387,785 were particularly effective at inhibiting growth of cells containing L718Q or L844V, and this was mirrored by inhibition of EGFR phosphorylation.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Gefitinib was moderately effective against L718Q and L844V models, with greater efficacy in the L844V model.

    “Gefitinib, a reversible quinazoline EGFR inhibitor, was moderately effective, with greater efficacy in the L844V model (Figure 1C and Table S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In PC9 GR cells expressing EGFR del E746_A750/T790M/L718Q or L844V, AZD9291 inhibited EGFR and downstream signaling phosphorylation, whereas WZ4002 and CO-1686 did not.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unlike the L858R counterpart, Del 19/T790M/C797S exists predominantly as a monomer and cetuximab treatment had no effect on EGFR phosphorylation or cell growth.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In an ENU mutagenesis assay using EGFR L858R Ba/F3 cells, gefitinib selected only T790M-containing clones, while WZ4002 selected only L718Q-containing clones.

    “With gefitinib we only recovered EGFR T790M containing clones while with WZ4002 only L718Q containing clones were recovered (Figure 2F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Engineered EGFR Del E746_A750/L718Q Ba/F3 cells, but not L858R/L718Q cells, showed a growth disadvantage.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cells with the Q791R mutation were relatively resistant to WZ4002 and CO-1686 but remained sensitive to AZD9291 and afatinib.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The EGFR mutations L718Q, L844V, and C797S each confer resistance to WZ4002 and CO-1686.

    “EGFR L718Q, L844V and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TX2-30 labeled mutant EGFR proteins more efficiently than wild-type EGFR, consistent with the mutant selectivity of WZ4002.

    “TX2-30 labeled the mutant EGFR proteins more efficiently than WT, consistent with the ‘mutant’ selectivity exhibited by the parental WZ4002 compound (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both L718Q and L844V mediate resistance to CO-1686.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The two classes of EGFR inhibitors (mutant-selective and quinazoline-based) are effective against non-cross-resistant mutations and together prevent the emergence of resistant clones.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    L718Q and L844V are not oncogenic.

    “These mutations are not oncogenic but mediate drug resistance likely through steric hindrance and impact drug binding (Figure 2A–C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The paper identifies secondary EGFR mutations L718Q and L844V, which occur more frequently in WZ4002- and CO-1686-resistant models.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The T790M EGFR mutation is the most common acquired resistance mechanism, found in about 60% of patients.

    “The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation in EGFR at position T790 (T790M)(10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients, afatinib is effective only in EGFR TKI-naive EGFR-mutant cancers and has a response rate below 10% in NSCLC that has become resistant to gefitinib or erlotinib.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Some EGFR mutant proteins, including L858R/T790M, do not require dimerization for oncogenic transformation.

    “Prior studies have demonstrated that some EGFR mutant proteins, including L858R/T790M, do not require dimerization for oncogenic transformation (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    L718Q likely interferes sterically with WZ4002 binding, while L844V likely removes favorable contacts with the inhibitor.

    “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).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All constructs were confirmed by DNA sequencing.

    “All constructs were confirmed by DNA sequencing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Clonogenic assays used three wells per point and were repeated at least twice.

    “All experimental points were set up in three wells and all experiments were repeated at least twice.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Other EGFR mutants, including EGFR L858R, require dimerization and are sensitive to cetuximab, which disrupts EGFR dimerization.

    “In contrast, other mutants, including EGFR L858R, require dimerization and are sensitive to the anti-EGFR antibody cetuximab which disrupts EGFR dimerization (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The crystal structure of WZ4002 bound to EGFR T790M shows that L718 and L844 directly contact the inhibitor, with L718 contacting the aniline ring and L844 contacting the pyrimidine ring.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The irreversible pyrimidine EGFR inhibitors WZ4002, CO-1686, and AZD9291 are more potent against T790M and selectively inhibit mutant over wild-type EGFR, which should improve efficacy and reduce toxicity compared with afatinib.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source

      Not checked in the free run.

    • cites [15] Walter, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov source

      Not checked in the free run.

    • cites [16] Cross, 2014, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C797 is the covalent binding site of WZ4002, and mutation to serine was previously shown to cause resistance.

    “C797 is the site of covalent binding of WZ4002 and previously demonstrated to lead to drug resistance if mutated to serine (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All cell lines were authenticated in September 2014 using the Promega Geneprint 16 cell ID system.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductown data

    The colony formation experiment was repeated three independent times.

    “The experiment was repeated three independent times.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Growth assays used six wells per experimental point and were repeated at least three times.

    “All experimental points were set up in six wells and all experiments were repeated at least three times.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    L718P, L718V, and L718M mutations have been described, but L718Q has not.

    “Mutations at L718 resulting in L718P, L718V and L718M mutations have been described but not EGFR L718Q (28–31).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [31] Munfus-McCray, 2013, Comparison of EGFR and KRAS mutations in primary and unpaired metastatic lung adenocarcinoma with potential chemotherapy effect, Human Pathol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The L844V mutation has been observed in a patient with NSCLC.

    “The L844V mutation has been previously observed in a NSCLC patient (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Zhou, 2010, A structure-guided approach to creating covalent FGFR inhibitors, Chem Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    L718Q and L844V impair WZ4002 binding to EGFR.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CO-1686 is structurally more closely related to WZ4002 than to AZD9291, and in all models tested CO-1686 is very similar in vitro to WZ4002.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Zhou, 2009, Novel mutant-selective EGFR kinase inhibitors against EGFR T790M, Nature source

      Not checked in the free run.

    • cites [15] Walter, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov source

      Not checked in the free run.

    • cites [16] Cross, 2014, AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer, Cancer Discov source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Given the increased ATP affinity imparted by T790M, it may not be possible to identify a non-covalent EGFR inhibitor with sufficient affinity to inhibit EGFR in the presence of mutations in C797, and hence an alternative approach may be necessary.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    L718Q and L844V mediate drug resistance likely through steric hindrance and impact drug binding.

    “These mutations are not oncogenic but mediate drug resistance likely through steric hindrance and impact drug binding (Figure 2A–C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Additional preclinical studies have identified activation of MAPK signaling, IGF1R signaling, and epithelial-to-mesenchymal transition as potential resistance mechanisms to WZ4002 and CO-1686.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Walter, 2013, Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC, Cancer Discov source

      Not checked in the free run.

    • cites [19] Ercan, 2012, Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors, Cancer Discov source

      Not checked in the free run.

    • cites [20] Cortot, 2013, Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway, Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    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 AZD9291 or CO-1686.

    “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.”
    Quote in the paperSubstantial claim
    • 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.
43 of 43

  • 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.”
7 of 7

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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
Publisher
American Association for Cancer Research (AACR)
Published
2015-08-31
Volume
21
Issue
17
Pages
3913-3923
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-14-2789
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
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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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