Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance Journal Article


Authors: Yu, H. A.; Suzawa, K.; Jordan, E.; Zehir, A.; Ni, A.; Kim, R.; Kris, M. G.; Hellmann, M. D.; Li, B. T.; Somwar, R.; Solit, D. B.; Berger, M. F.; Arcila, M.; Riely, G. J.; Ladanyi, M.
Article Title: Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance
Abstract: Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing. Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR 1⁄4 2.4, P 1⁄4 0.015) or MET (HR 1⁄4 3.7, P 1⁄4 0.019), or mutation in TP53 (HR 1⁄4 1.7, P 1⁄4 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 13
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-07-01
Start Page: 3108
End Page: 3118
Language: English
DOI: 10.1158/1078-0432.ccr-17-2961
PROVIDER: scopus
PUBMED: 29530932
DOI/URL:
Notes: Article -- Export Date: 1 August 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. David Solit
    431 Solit
  2. Helena Alexandra Yu
    88 Yu
  3. Marc Ladanyi
    861 Ladanyi
  4. Gregory J Riely
    344 Riely
  5. Romel Somwar
    34 Somwar
  6. Ahmet Zehir
    149 Zehir
  7. Michael Forman Berger
    380 Berger
  8. Maria Eugenia Arcila
    336 Arcila
  9. Mark Kris
    597 Kris
  10. Matthew David Hellmann
    161 Hellmann
  11. Emmet John Jordan
    29 Jordan
  12. Bob Tingkan Li
    58 Li
  13. Ai   Ni
    47 Ni
  14. Ken Suzawa
    4 Suzawa