KRAS Inhibitor Resistance in MET -Amplified KRAS G12C Non-Small Cell Lung Cancer Induced By RAS- and Non-RAS-Mediated Cell Signaling Mechanisms.

Purpose: Treatment with KRAS ^G12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRAS ^G12C NSCLC cells.
Experimental Design: Clones of sotorasib-sensitive KRAS ^G12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy-number evaluation. The underlying mechanisms of resistance were investigated using immunologic examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo .
Results: Unbiased screening detected subclonal evolution of MET amplification in KRAS ^G12C NSCLC cells that had developed resistance to sotorasib in vitro . MET knockdown using small interfering RNA (siRNA) restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/ KRAS ^G12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice.
Conclusions: MET amplification leads to the development of resistance to KRAS ^G12C inhibitors in NSCLC. Dual blockade of MET and KRAS ^G12C could be a treatment option for MET -amplified, KRAS ^G12C -mutated NSCLC.
(©2021 American Association for Cancer Research.)