KRAS Inhibitor Resistance in MET-Amplified KRASG12C Non–Small Cell Lung Cancer Induced By RAS- and Non–RAS-Mediated Cell Signaling Mechanisms

Abstract

Purpose: Treatment with KRASG12C 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 KRASG12C NSCLC cells. Experimental Design: Clones of sotorasib-sensitive KRASG12C 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 KRASG12C 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/KRASG12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice. Conclusions: MET amplification leads to the development of resistance to KRASG12C inhibitors in NSCLC. Dual blockade of MET and KRASG12C could be a treatment option for MET-amplified, KRASG12C-mutated NSCLC.

Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer

“…In the preclinical setting, Suzuki et al exposed mutant KRAS G12C cells to sotorsaib finding MET amplifications in resistant cells. To further confirm this as the resistance mechanisms, they demonstrated thar after MET knockdown using siRNA, cells recovered sensitivity to sotorasib (46). Moreover, they found that MET amplified cells had higher levels of GTP-bound (active) RAS, mainly in other isoforms such as NRAS, suggesting that MET amplification could confer resistance by the reactivation of RAS-BRAF-MEK-ERK pathway by direct activation of other RAS isoforms.…”

“…A main mechanism of primary resistance is feedback reactivation mediated by multiple RTKs, leading to preclinical research aiming to combine the inhibition of KRAS G12C and other RTKs such as EGFR, FGFR, and MET (56). In this setting the combination of sotorasib and MET inhibitors such as crizotinib and capmatinib has shown to overcome resistance to KRAS G12C inhibitors in vitro in cancer cells with MET amplification (46). One of the main focuses of current development is targeting transduction molecules situated downstream from RTKs such as SHP2 and SOS1 which after phosphorylation favor de GTP-bound state thus activating the ERK pathway (57).…”

“…Preclinical research showed that the combination of a KRAS G12C inhibition (ARS-1620) with a SHP2 inhibitor (SHP099) conveyed a more profound suppression of KRAS-GTP and total RAS-GTP in vitro and enhance tumor regression in xenograft models compared to ARS-1620 and SHP099 alone (39). In the same manner the combination of sotorasib and BI-3406, a SOS1 inhibitor, resulted in diminished activity of the ERK pathway in KRAS G12C mutant cells (46). Multiple clinical trials are ongoing to test the efficacy of the combination of KRAS G12C and SHP2 inhibitors including: the phase 1/2 KRYSTAL 2 trial evaluating the combination of MRTX849 and TNO155 in patients with solid tumor with KRAS G12C mutation (NCT04330664) and a phase Ib/II evaluating JDQ443 (KRAS G12C inhibitor) and TNO155 (NCT04699188).…”

Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma

“…Ras—a small-molecule GTPase member—has important regulatory functions in cell signal transduction, cytoplasmic skeletal construction, and material transport ( Ostrem et al, 2013 ; Lim et al, 2014 ; Lito et al, 2016 ). Notably, recent findings indicated that the Ras gene was mutated in more than 30% of HCC-afflicted patients sampled ( Guichard et al, 2012 ; Lindsay and Blackhall, 2019 ; Suzuki et al, 2021 ). Mutations in the Ras gene have also been detected in various other types of cancers as well, including those for lung cancer, pancreatic cancer, and colon cancer ( Zhang et al, 2018 ; Zhao et al, 2018 ; Chen et al, 2020 ).…”

DataSheet1.PDF

“…Ras-a small-molecule GTPase member-has important regulatory functions in cell signal transduction, cytoplasmic skeletal construction, and material transport (Ostrem et al, 2013;Lim et al, 2014;Lito et al, 2016). Notably, recent findings indicated that the Ras gene was mutated in more than 30% of HCC-afflicted patients sampled (Guichard et al, 2012;Lindsay and Blackhall, 2019;Suzuki et al, 2021). Mutations in the Ras gene have also been detected in various other types of cancers as well, including those for lung cancer, pancreatic cancer, and colon cancer (Zhang et al, 2018;Zhao et al, 2018;Chen et al, 2020).…”