EGFR Blockade Reverts Resistance to KRAS(G12C) Inhibition in Colorectal Cancer

Vito Amodio, Rona Yaeger, Pamela Arcella, Carlotta Cancelliere, Simona Lamba, Annalisa Lorenzato, Sabrina Arena, Monica Montone, Benedetta Mussolin, Yu Bian, Adele Whaley, Marika Pinnelli, Yonina R Murciano-Goroff, Efsevia Vakiani, Nicola Valeri, Wei-Li Liao, Anuja Bhalkikar, Sheeno Thyparambil, Hui-Yong Zhao, Elisa de StanchinaSilvia Marsoni, Salvatore Siena, Andrea Bertotti, Livio Trusolino, Bob T Li, Neal Rosen, Federica Di Nicolantonio, Alberto Bardelli, Sandra Misale

Research output: Contribution to journalArticlepeer-review

Abstract

Most patients with KRASG12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer. SIGNIFICANCE: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079.

Original languageEnglish
Pages (from-to)1129-1139
Number of pages11
JournalCancer Discovery
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 2020

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