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

Abstract

Purpose: To identify novel mechanisms of resistance to thirdgeneration 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 KRAS G12S 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.

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

“…Among the 43 patients, 11 (26%) had MET amplifications; of these, 7 patients presented only MET amplification, 3 had also SNV in other genes (PIK3CA and CDKN2A) and 1 presented concurrent HER2 amplification, similarly to Ortiz-Cuaran et al (13). The authors, analyzing an expanded cohort of 16 patients T790M-positive and with MET copy number gain in pre-treatment biopsies or plasma, observed that this group displayed significantly less tumor shrinkage and shorter median progression-free survival (PFS) than patients without MET alterations.…”

“…Also Ortiz-Cuaran et al showed high-level amplification of MET either in tumor biopsy collected before treatment in a patient that experienced primary resistance to rociletinib and in the post-treatment biopsy of a patient that developed resistance after stable disease to osimertinib (13). Thanks to in vitro models they could provide functional evidence that HER2 and MET amplification may induce innate and acquired resistance to this new class of EGFR inhibitors, confirming clinical observations (13).…”

“…Ortiz-Cuaran et al described in their cohort two cases of HER2 amplification (13). In a patient treated with rociletinib HER2 amplification was detectable already after three weeks of treatment, while for the patient treated with osimertinib was detectable in lung sample biopsy collected before treatment.…”

“…Ortiz-Cuaran and colleagues described a patient treated with osimertinib that presented p.C797S in a plasma sample with corresponding re-biopsy C797S and T790M-negative but KRAS G12S-positive (13). EGFR inhibition through osimertinib may functionally deplete oncogenic EGFR signaling to a level that would allow the emergence of cells harboring KRAS mutations.…”

Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when?

“…Preclinical studies have also identified potential resistance mechanisms. For example, cells that are resistant to osimertinib appear to have enhanced levels of phosphorylated MEK and may be particularly sensitive to combined EGFR and MEK inhibition [57,58]. The identification of heterogeneous resistance mechanisms to osimertinib has prompted the initiation of several early-phase clinical trials [59].…”