Journal
CLINICAL CANCER RESEARCH
Volume 27, Issue 20, Pages 5697-5707Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-0856
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Funding
- Japan Society for the Promotion of Science KAKENHI [21K07204]
- Grants-in-Aid for Scientific Research [21K07204] Funding Source: KAKEN
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The study identified MET amplification as a mechanism of resistance to KRAS(G12C) inhibitors in NSCLC. Using MET inhibitor Crizotinib restored sensitivity to sotorasib, and dual inhibition of MET and KRAS(G12C) led to tumor shrinkage in sotorasib-resistant xenograft mice.
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.
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