Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models

TLDR

Resistance to targeted EGFR inhibitors is likely to develop in EGFR‑mutant lung cancers, and early identification of innate or acquired resistance mechanisms is essential to guide future therapies. The study aims to detect heterogeneous resistance mechanisms in EGFR‑mutant PC9 and NCI‑H1975 cell populations that have acquired resistance to EGFR tyrosine kinase inhibitors, including AZD9291. The authors examined these cell lines to identify diverse resistance mechanisms, focusing on genetic alterations and signaling dependencies. They identified NRAS mutations (including a novel E63K) and copy‑number gains of WT NRAS or KRAS in resistant cells, and demonstrated that combining AZD9291 with the MEK inhibitor selumetinib prevented or delayed resistance in vitro and induced regression of resistant tumors in vivo, supporting combined EGFR/MEK therapy. Published in Cancer Research 75(12):2489–2500; ©2015 AACR.

Abstract

Abstract Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. Cancer Res; 75(12); 2489–500. ©2015 AACR.