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Cited by 490Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Structure-based classification predicts drug response in EGFR-mutant NSCLC

Open access
Robichaux, Jacqulyne P., Le, Xiuning, Vijayan, R. S. K., Hicks, J. Kevin, Heeke, Simon, Elamin, Yasir Y., Lin, Heather Y., Udagawa, Hibiki +25 more·2021·Nature
DOI 10.1038/s41586-021-03898-1PMC PMC8481125
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Abstract

Epidermal growth factor receptor ( EGFR ) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC) 1–3 . Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations 4–6 . However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown 1,3,7–10 . Here we characterize the mutational landscape in 16,715 patients with EGFR -mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR -mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.

AI snapshot

Written from the paper’s full text.

TL;DR

In 16,715 patients with EGFR-mutant NSCLC, atypical EGFR mutations were common and associated with worse TKI outcomes than classical mutations. EGFR mutations could be classified into four structure–function subgroups that retrospectively predicted drug sensitivity and patient outcomes better than exon-based grouping.

Key findings

  • Among 11,619 patients with per-patient mutation data, 67.1% had classical EGFR mutations, 30.8% had atypical mutations (including Ex20ins 9.1%, atypical mutations 12.6%, and complex mutations including an atypical mutation 9.1%), and 2.2% had a classical mutation with T790M and an atypical mutation. Atypical mutations (n = 7,199) occurred primarily in exon 18 (23.7%) and exon 20 (20.9% insertions and 19.2% point mutations), with hotspots in the P-loop (13.6%) and the C-terminal loop of the αC-helix (29.4%).
  • Patients with atypical EGFR mutations had shorter time to treatment failure (TTF) than those with classical mutations (HR = 1.8, P < 0.0001), including when Ex20ins were excluded (HR = 1.6, P < 0.0001), with first-generation TKIs (HR = 1.9, P = 0.0005), and with third-generation TKIs (HR = 3.0, P < 0.0001); the second-generation TKI difference was not significant (HR = 1.7, P = 0.10).
  • EGFR mutations separated into four subgroups—classical-like, T790M-like, Ex20ins-L, and PACC—and structure–function groups were more predictive of drug sensitivity than exon-based groups (P < 0.0001 by correlation and by CART variable importance; without T790M, P = 0.0034 and P < 0.0001, respectively).
  • PACC mutations were more sensitive to second-generation TKIs: PACC patients had longer afatinib duration of treatment (17.1 months, P < 0.0001), and PACC patients treated with second-generation TKIs had longer TTF than those treated with first- or third-generation TKIs (21.7 months versus 10.0 and 4.1 months; P < 0.0001, HR = 0.23). PACC patients also had longer TTF than non-PACC patients on second-generation TKIs (21.7 versus 10.0 months; HR = 2.6, P = 0.0068).

Methods

  • Retrospective genomic and clinical analyses used five patient databases (MD Anderson GEMINI, Foundation Medicine, Guardant Health, cBioPortal, and Moffitt Cancer Center), representing 16,715 patients with EGFR-mutant NSCLC; outcomes included TTF, overall survival, progression-free interval, and afatinib response/duration from the Uncommon EGFR Database (803 patients; ORR reported in 529; duration in 746).
  • In vitro drug screening used 76 Ba/F3 cell lines expressing EGFR mutations spanning exons 18–21 against 18 EGFR inhibitors, with mutant/WT IC50 ratios, hierarchical clustering, Spearman correlations, and CART analysis; an additional 15 Ba/F3 lines expressing Ex20ins-L mutations were used to define near- versus far-loop insertions.
  • In vivo validation used patient-derived xenografts and case studies; in silico mutational mapping and docking modeled structural effects. Statistical analyses included Kaplan–Meier methods, two-sided Mantel–Cox log-rank tests, ANOVA, Fisher’s exact test, and paired t-tests.

Limitations

  • Stated: no sample size calculations were done to predetermine group sizes, and investigators were not blinded during randomization and outcome assessments. The databases are enriched in North American patients, so atypical EGFR mutation frequency may differ in Asia or other regions. TTF was not based on RECIST criteria.
  • Stated: clinical validation of different drugs for each individual mutation was considered not feasible; the proposed classification groups mutations rather than testing every mutation–drug pair.
  • Evident from the text: key clinical comparisons are retrospective, and the structure–function classification is supported by in vitro Ba/F3 models, in silico modeling, PDX experiments, and retrospective patient databases rather than prospective randomized trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-021-03898-1

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups.

    “We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups.”
    • Also stated in: § Discussion · plain
      “We show that EGFR mutations, including atypical mutations, can be divided into four distinct subgroups based on structure and function (Fig. 5), and that structure–function-based groups can predict drug sensitivity and patient outcomes better than exon-based groups.”
    Quote in the paperSubstantial claim
  • Findingcitation

    In the cBioPortal database, patients with atypical EGFR mutations had a shorter progression free interval and overall survival, irrespective of treatment.

    “Validating these findings in the cBioPortal database, patients with atypical EGFR mutations had a shorter progression free interval19 and overall survival, irrespective of treatment (Extended Data Fig. 1g, h).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Liu, J. et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 173, 400–416.e411 (2018). source

      Not checked in the free run.

  • Findingown data

    Structure-function-based groups were more predictive of mutation sensitivity than exon-based groups (P < 0.0001).

    “We found that structure–function-based groups were more predictive of mutation sensitivity than exon-based groups (P < 0.0001) (Fig. 2b).”
    Quote in the paperSubstantial claim
  • Findingown data

    Structure-function-based groups had a higher variable importance than exon-based groups in CART analysis (P < 0.0001).

    “Structure–function-based groups had a higher variable importance than exon-based groups”
    Quote in the paperSubstantial claim
  • Findingown data

    Among 11,619 patients with primary and/or co-occurring mutations recorded on a per-patient basis, 67.1% had classical EGFR mutations.

    “Among those patients, 67.1% had classical EGFR mutations (L858R and/or Ex19del with or without T790M)”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 17
  • May combine two claims. 33

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

    Findingown data

    2.2% of patients had a classical mutation with T790M and an atypical mutation.

    “and 2.2% had a classical mutation with T790M and an atypical mutation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For second-generation TKIs, a similar trend of longer TTF for classical versus atypical EGFR mutations was observed but was not statistically significant (HR = 1.7, P = 0.10).

    “A similar trend was observed for second-generation TKIs; however, the difference was not statistically significant (HR = 1.7, P = 0.10)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The atypical EGFR mutation group comprised Ex20ins (9.1%), atypical mutations (12.6%), and complex mutations including an atypical mutation (9.1%).

    “including Ex20ins (9.1%), atypical mutations (12.6%), or a complex mutation including an atypical mutation (9.1%)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Prevalent hotspots for atypical mutations were the P-loop (L718-V726, 13.6%) and the C-terminal loop of the αC-helix (A767-G779, 29.4%).

    “Prevalent hotspots for atypical mutations were the P-loop (L718–V726, 13.6%) and the C-terminal loop of the αC-helix (A767–G779, 29.4%, Fig. 1c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PACC mutations comprise mutations spanning exons 18-21 including G719X, L747X, S768I, L792X and T854I and were predicted to alter the orientation of the P-loop or αC-helix.

    “PACC mutations comprise mutations spanning exons 18–21 including G719X, L747X, S768I, L792X and T854I and were predicted to alter the orientation of the P-loop or αC-helix (Extended Data Fig. 8a, b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    L718Q, S768I, and T854I correspond to exons 18, 20, and 21, respectively, but are all PACC mutations with similar structural effects on drug binding.

    “For example, L718Q, S768I, and T854I correspond to exons 18, 20, and 21, respectively, but are all PACC mutations with similar structural effects on drug binding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    T790M-like-3R mutants, complex mutations comprising T790M and a known drug-resistance mutation, were resistant to classical EGFR TKIs but retained selectivity for select ALK and PKC inhibitors such as brigatinib or midostaurin.

    “T790M-like-3R mutants, complex mutations comprising T790M and a known drug-resistance mutation (that is, C797S30, L718X31 or L792H18,31), were resistant to classical EGFR TKIs but retained selectivity for select ALK and PKC inhibitors such as brigatinib or midostaurin (Extended Data Fig. 7c).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015). source

      Not checked in the free run.

    • cites [31] Ou, S. I. et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer 108, 228–231 (2017). source

      Not checked in the free run.

    • cites [18] Le, X. et al. Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC. Clin. Cancer Res. 24, 6195–6203 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Structure-function-based grouping showed clear differences between sensitive (classical-like and PACC) and resistant (T790M-like and Ex20ins-L) subgroups (ORR of 63% versus 20%), whereas exon-based groups had less variation between groups.

    “Structure–function-based grouping showed clear differences between sensitive (classical-like and PACC) and resistant (T790M-like and Ex20ins-L) subgroups (ORR of 63% versus 20%), whereas exon-based groups had less variation between groups (Extended Data Fig. 10a, b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    L747_K754del-insATSPE, L747P and E746-A750del mutations occur in exon 19 but are T790M-like, PACC, and classical mutations, respectively, with distinct drug sensitivity and structural effects.

    “Conversely, mutations within the same exon may induce quite disparate changes. L747_K754del-insATSPE, L747P and E746-A750del mutations occur in exon 19 but are T790M-like, PACC, and classical mutations, respectively, with distinct drug sensitivity and structural effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Without T790M mutations, structure-function-based groups remained more predictive of mutation and drug sensitivity than exon-based groups (P = 0.0034 and P < 0.0001, respectively).

    “We validated these findings without T790M mutations (Extended Data Fig. 4c, d), and structure–function-based groups remained more predictive of mutation and drug sensitivity than exon-based groups (P = 0.0034 and P < 0.0001, respectively) (Extended Data Fig. 4e, f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    T790M-like-3S mutants had high selectivity for third-generation TKIs and some Ex20ins-active inhibitors and moderate selectivity for ALK and PKC inhibitors.

    “T790M-like-3S mutants had high selectivity for third-generation TKIs and some Ex20ins-active inhibitors and moderate selectivity for ALK and PKC inhibitors (Extended Data Fig. 7b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Exon 20 near-loop insertions (Ex20ins-NL) were more sensitive to second-generation and Ex20ins-active TKIs compared with exon 20 far-loop insertions (Ex20ins-FL) (P = 0.0025 and P = 0.027, respectively).

    “Exon 20 near-loop insertions (Ex20ins-NL) were more sensitive to second-generation and Ex20ins-active TKIs compared with exon 20 far-loop insertions (Ex20ins-FL) (P = 0.0025 and P = 0.027, respectively) (Extended Data Fig. 6e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two of these patients acquired a L718V mutation, and one acquired two PACC mutations (V765L and C797S).

    “Two patients acquired a L718V mutation, and one acquired two PACC mutations (V765L and C797S).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    C797S mutations without T790M conferred resistance to Ex20ins-active inhibitors, but not first- or second-generation TKIs unless T790M was present.

    “Similarly, C797S mutations without T790M conferred resistance to Ex20ins-active inhibitors, but not first- or second-generation TKIs unless T790M was present (Fig. 3e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NSCLC patient-derived xenografts containing G719A mutations were resistant to osimertinib but most sensitive to poziotinib.

    “In vivo, we also observed that NSCLC patient-derived xenografts (PDXs) containing G719A mutations were resistant to the third-generation TKI osimertinib, but most sensitive to the second-generation TKI poziotinib (Fig. 3b, Extended Data Fig. 8f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using mutational mapping, EGFR mutations were separated into four distinct groups based on predicted drug sensitivity: (1) no obvious effect on the drug binding pocket; (2) a mutation in the hydrophobic core; (3) a large inward shift of both the αC-helix and P-loop; and (4) a slight inward shift of the αC-helix and/or P-loop.

    “Using mutational mapping there were four distinct groups: (1) no obvious effect on the drug binding pocket (similar to L858R); (2) a mutation in the hydrophobic core (similar to T790M); (3) a large inward shift of both the αC-helix and P-loop (similar to exon 20 insertions); and (4) a slight inward shift of the αC-helix and/or P-loop”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All three patients were treated with a second-generation TKI and experienced clinical benefits of stable disease and tumour shrinkage.

    “All patients were treated with a second-generation TKI and experienced clinical benefits of stable disease and tumour shrinkage (Extended Data Fig. 9a–c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acquired PACC mutations co-occurring with primary classical EGFR mutations retained sensitivity to second-generation TKIs while acquiring resistance to third-generation TKIs in an allele-specific manner.

    “Similarly, acquired PACC mutations co-occurring with primary classical EGFR mutations retained sensitivity to second-generation TKIs while acquiring resistance to third-generation TKIs in an allele-specific manner (Fig. 3c, d).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The frequency and effects of atypical EGFR mutations on drug sensitivity are unknown.

    “Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7–10.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [1] Russo, A. et al. Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int. J. Mol. Sci. 20, 1431 (2019). source

      Not checked in the free run.

    • cites [3] Klughammer, B. et al. Examining treatment outcomes with erlotinib in patients with advanced non-small cell lung cancer whose tumors harbor uncommon EGFR mutations. J. Thorac. Oncol. 11, 545–555 (2016). source

      Not checked in the free run.

    • cites [7] Yoshikawa, S. et al. Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene 32, 27–38 (2013). source

      Not checked in the free run.

    • cites [8] Massarelli, E., Johnson, F. M., Erickson, H. S., Wistuba, I. I. & Papadimitrakopoulou, V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 80, 235–241 (2013). source

      Not checked in the free run.

    • cites [9] Yasuda, H., Kobayashi, S. & Costa, D. B. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 13, e23–e31 (2012). source

      Not checked in the free run.

    • cites [10] Kosaka, T. et al. Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors. Cancer Res. 77, 2712–2721 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical trial design and treatment of patients with atypical EGFR mutations often rely on mutated-exon location to predict treatment, although heterogeneity in drug sensitivity across a single exon has been observed.

    “Clinical trial design and treatment of patients with atypical EGFR mutations often rely on mutated-exon location to predict treatment, although heterogeneity in drug sensitivity across a single exon has been observed1,8,17.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Russo, A. et al. Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int. J. Mol. Sci. 20, 1431 (2019). source

      Not checked in the free run.

    • cites [8] Massarelli, E., Johnson, F. M., Erickson, H. S., Wistuba, I. I. & Papadimitrakopoulou, V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 80, 235–241 (2013). source

      Not checked in the free run.

    • cites [17] Shi, J. et al. Uncommon EGFR mutations in a cohort of Chinese NSCLC patients and outcomes of first-line EGFR-TKIs and platinum-based chemotherapy. Chin. J. Cancer Res. 29, 543–552 (2017). source

      Not checked in the free run.

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

    Premisecitation

    Other EGFR mutations in the kinase domain (exons 18−21) have also been established as oncogenic drivers of NSCLC.

    “Other EGFR mutations in the kinase domain (exons 18−21) have also been established as oncogenic drivers of NSCLC8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Massarelli, E., Johnson, F. M., Erickson, H. S., Wistuba, I. I. & Papadimitrakopoulou, V. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. Lung Cancer 80, 235–241 (2013). source

      Not checked in the free run.

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

    Premisecitation

    EGFR mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC).

    “Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC)1–3.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Russo, A. et al. Heterogeneous responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations: new insights and future perspectives in this complex clinical scenario. Int. J. Mol. Sci. 20, 1431 (2019). source

      Not checked in the free run.

    • cites [2] Kobayashi, Y. et al. EGFR exon 18 mutations in lung cancer: molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs. Clin. Cancer Res. 21, 5305–5313 (2015). source

      Not checked in the free run.

    • cites [3] Klughammer, B. et al. Examining treatment outcomes with erlotinib in patients with advanced non-small cell lung cancer whose tumors harbor uncommon EGFR mutations. J. Thorac. Oncol. 11, 545–555 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atypical EGFR mutations with FDA-approved treatments are EGFR S768I, L861Q and G719X, for which afatinib was deemed effective on the basis of retrospective studies, and the EGFR/MET bispecific antibody amivantamab for exon 20 insertions.

    “Atypical EGFR mutations with US Food and Drug Administration (FDA)-approved treatments are EGFR S768I, L861Q and G719X, for which afatinib was deemed effective on the basis of retrospective studies13–15, and the EGFR/MET bispecific antibody amivantamab for exon 20 insertions (Ex20ins)16.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [13] Wu, Y. L. et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 15, 213–222 (2014). source

      Not checked in the free run.

    • cites [14] Yang, J. C. et al. 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. 16, 830–838 (2015). source

      Not checked in the free run.

    • cites [15] Yang, J. C. et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16, 141–151 (2015). source

      Not checked in the free run.

    • cites [16] Administration, U. S. F. a. D. (ed FDA) (2021).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Targeted therapies are approved for patients with classical EGFR mutations and a small number of other mutations.

    “Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations4–6.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239–246 (2012). source

      Not checked in the free run.

    • cites [5] Sequist, L. V. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3327–3334, https://doi.org/10.1200/JCO.2012.44.2806 (2013). source

      Not checked in the free run.

    • cites [6] Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018). source

      Not checked in the free run.

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

    Study design and conductcitation

    PDXs were generated and maintained in accordance with Good Animal Practices and with approval from MD Anderson Cancer Center Institutional Animal Care and Use Committee on protocol number PA140276.

    “PDXs harbouring EGFR G719A and EGFR L858R/E709K were generated and maintained in accordance with Good Animal Practices and with approval from MD Anderson Cancer Center Institutional Animal Care and Use Committee on protocol number PA140276 as previously described46.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Chen, Y. et al. Tumor characteristics associated with engraftment of patient-derived non-small cell lung cancer xenografts in immunocompromised mice. Cancer 125, 3738–3748 (2019). source

      Not checked in the free run.

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

    Study design and conductnone given

    Data collection for Moffitt Cancer Center patients was performed under protocol MCC 19161, which was formally reviewed and granted approval by MCC in accordance with the Declaration of Helsinki and the 21st Century Cures Act.

    “Data collection for Moffitt Cancer Center (MCC) patients was performed under the protocol (MCC 19161), which was formally reviewed and granted approval by MCC in accordance with the Declaration of Helsinki and the 21st Century Cures Act.”
    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

    Most patients (80%) were stage IV at diagnosis, and there were no statistical differences in patient characteristics.

    “Most patients (80%) were stage IV at diagnosis, and there were no statistical differences in patient characteristics (Supplementary Tables 5, 6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Structure-function-based groups can identify classes of drugs that may be effective for whole groups of mutations, reflecting the observation that mutations in different regions of the gene may induce similar changes in protein structure.

    “These findings demonstrate that structure–function-based groups can identify classes of drugs that may be effective for whole groups of mutations, reflecting the observation that mutations in different regions of the gene may induce similar changes in protein structure.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Mice were randomized into treatment groups when tumors reached a specified volume.

    “Tumours were measured 3 times per week and were randomized into treatment groups when tumors reached a volume of 275–325 mm3 for the EGFR G719A and S768dupSVD models, and 150–175 mm3 for the L858R/E709K model.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Tumours were validated for EGFR mutations by DNA fingerprinting and quantitative PCR.

    “Tumours were validated for EGFR mutations by DNA fingerprinting and quantitative PCR as described46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Chen, Y. et al. Tumor characteristics associated with engraftment of patient-derived non-small cell lung cancer xenografts in immunocompromised mice. Cancer 125, 3738–3748 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    For cancers containing oncogenes with diverse mutations, adopting a structure-function-based approach may improve clinical trial design and drug development.

    “Finally, these findings support the notion that for cancers containing oncogenes with diverse mutations, adopting a structure–function-based approach may improve clinical trial design and drug development.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The Guardant360 clinical database and the four datasets reported here are enriched in North American patients with NSCLC, and the frequency of atypical EGFR mutations may differ in Asia or other regions.

    “The Guardant360 clinical database, and the four datasets reported here, are enriched in North American patients with NSCLC; the frequency of atypical EGFR mutations may differ in Asia or other regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Mutations within an exon are heterogenous and an exon-based classification is unlikely to be optimal for guiding treatment decisions.

    “These data exemplify that mutations within an exon are heterogenous and that an exon-based classification is unlikely to be optimal for guiding treatment decisions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Structure-function classification identified not only a larger subgroup of patients, but also a subgroup with greater benefit from second-generation TKIs than the exon-based classification.

    “Therefore, structure–function classification identified not only a larger subgroup of patients, but also a subgroup with greater benefit from second-generation TKIs than the exon-based classification.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    EGFR mutations were determined from formalin-fixed paraffin-embedded tumours or digital-droplet PCR for blood samples by CLIA-certified methods.

    “EGFR mutations were determined from formalin-fixed paraffin-embedded tumours or digital-droplet PCR for blood samples by CLIA-certified methods as previously described18,37.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Le, X. et al. Landscape of EGFR -dependent and -independent resistance mechanisms to osimertinib and continuation therapy post-progression in EGFR-mutant NSCLC. Clin. Cancer Res. 24, 6195–6203 (2018). source

      Not checked in the free run.

    • cites [37] Liu, X. et al. Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer. Lung Cancer 149, 33–40 (2020). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Patient samples in the Foundation Medicine database were subjected to hybrid-capture based comprehensive genomic profiling using previously validated assays.

    “patient samples taken between November 2011 and May 2020 previously subjected to hybrid-capture based comprehensive genomic profiling using formalin-fixed paraffin-embedded tissue or plasma using previously validated assays38,39”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023–1031 (2013). source

      Not checked in the free run.

    • cites [39] Clark, T. A. et al. Analytical validation of a hybrid capture-based next-generation sequencing clinical assay for genomic profiling of cell-free circulating tumor DNA. J. Mol. Diagn. 20, 686–702 (2018). source

      Not checked in the free run.

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

    Study design and conductnone given

    Patients were consented under the GEMINI protocol (PA13-0589) approved by the MD Anderson Institutional Review Board, or protocol MCC 19161 approved by Moffitt Cancer Center.

    “Patients were consented under the GEMINI protocol (PA13-0589) which was approved in accordance with the MD Anderson Institutional Review Board, or protocol MCC 19161, which was formally reviewed and granted approval by Moffitt Cancer Center in accordance with the Declaration of Helsinki and the 21st Century Cures Act for retrospective analysis of patient outcomes and treatment course for case stud”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The classification presented here provides a framework through which clinicians could more effectively personalize EGFR TKI therapy.

    “The classification presented here provides a framework through which clinicians, informed by internet-based tools or companies providing NGS reports, could more effectively personalize EGFR TKI therapy.”
    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 conductnone given

    No sample size calculations were done to predetermine group sizes, and investigators were not blinded during randomization and outcome assessments.

    “No sample size calculations were done to predetermine group sizes, and investigators were not blinded during randomization and outcome assessments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Second-generation TKIs were less affected by shifts in the hinge region and were predicted to maintain the orientation of the acrylamide group.

    “However, second-generation TKIs were less affected by shifts in the hinge region of the receptor and were predicted to maintain the orientation of the acrylamide group (Extended Data Fig. 8f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both primary and acquired PACC mutations are sensitive to second-generation TKIs, and structure-function-based groupings could identify a novel class of mutations, PACC mutations, for which second-generation TKIs had higher selectivity and efficacy than third-generation drugs.

    “These data demonstrate that both primary and acquired PACC mutations are sensitive to second-generation TKIs, and structure–function-based groupings could identify a novel class of mutations, PACC mutations, for which second-generation TKIs had higher selectivity and efficacy than third-generation drugs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Second-generation TKIs do not interact with the P-loop of EGFR and maintain interaction points in the hydrophobic cleft.

    “By contrast, second-generation TKIs do not interact with the P-loop of EGFR and maintain interaction points in the hydrophobic cleft (Extended Data Fig. 8d, e).”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    Effective therapies have not been identified for additional EGFR mutations.

    “However, effective therapies have not been identified for additional EGFR mutations.”

  • The paper relies on this without support.

    There are no clear established guidelines for EGFR TKI treatment for patients with atypical EGFR mutations without an FDA-approved TKI, often resulting in patients receiving chemotherapy.

    “There are no clear established guidelines for EGFR TKI treatment for patients with atypical EGFR mutations without an FDA-approved TKI, often resulting in patients receiving chemotherapy.”

  • The paper relies on this without support.

    Second-generation TKIs have limited activity in the central nervous system.

    “Unlike osimertinib, second-generation TKIs have limited activity in the central nervous system, demonstrating the need for novel TKIs with reduced inhibition of wild-type EGFR inhibition and CNS activity that can inhibit PACC mutants.”
3 of 3

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?

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.

  • Fig. 3 caption cites panels that are not listed

    Minor

    The Fig. 3 caption describes panels a through e, but its final sentence refers to panels f and h.

1 of 1

Cites

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Cited by

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Authors
Robichaux, J. P., Le, X., Vijayan, R. S. K., Hicks, J. K., Heeke, S., Elamin, Y. Y., Lin, H. Y., Udagawa, H., Skoulidis, F., Tran, H., Varghese, S., He, J., Zhang, F., Nilsson, M. B., Hu, L., Poteete, A., Rinsurongkawong, W., Zhang, X., Ren, C., Liu, X., Hong, L., Zhang, J., Diao, L., Madison, R., Schrock, A. B., Saam, J., Raymond, V., Fang, B., Wang, J., Ha, M. J., Cross, J. B., Gray, J. E., & Heymach, J. V.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Moffitt Cancer Center (US)
  • Foundation Medicine (United States) (US)
  • Guardant (United States) (US)
Corresponding author
Heymach, John V.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-09-15
Volume
597
Issue
7878
Pages
732-737
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03898-1
PMC
PMC8481125
OpenAlex
W3199928453
Cited by
490
References
44
Citations by year
2026: 98 · 2025: 117 · 2024: 105 · 2023: 86 · 2022: 72 · 2021: 11
FWCI
44.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Cancer Prevention and Research Institute of Texas (P50 CA070907, P30CA016672, CA016672)
  • American Society of Clinical Oncology
  • Spectrum Pharmaceuticals
  • National Institutes of Health (CA- 016672, CA-070907)
  • University of Texas MD Anderson Cancer Center ((CA016672), P30-CA-016672)
  • Foundation Medicine
  • National Cancer Institute (CA-070907, CA 016672, R01CA190628, R01CA234183, P50CA070907, U54CA224065, R01CA247975, P30CA016672, R50CA265307)
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, non-small cell lung cancer, EGFR inhibitors, drug response prediction, structural classification, mutational landscape, structure-function relationship, targeted therapy, clinical trial selection
MeSH terms
Afatinib, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Exons, Female, Humans, Lung Neoplasms, Mutation, Structure-Activity Relationship, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, Drug Repositioning, Molecular Docking Simulation, 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.

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