Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Clin Cancer Res. 2016 Oct 1;22(19):4837-4847. doi: 10.1158/1078-0432.CCR-15-1915. Epub 2016 Jun 1.

Abstract

Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).

Experimental design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS CONCLUSIONS: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837-47. ©2016 AACR.

MeSH terms

  • Acrylamides / therapeutic use
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma of Lung
  • Aged
  • Aniline Compounds / therapeutic use
  • Antineoplastic Agents / therapeutic use*
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Pyrimidines / therapeutic use

Substances

  • Acrylamides
  • Aniline Compounds
  • Antineoplastic Agents
  • Pyrimidines
  • osimertinib
  • rociletinib
  • EGFR protein, human
  • ErbB Receptors