Most patients with KRAS ^G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS^G12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS^G12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS ^G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS ^G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRAS^G12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRAS^G12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRAS^G12C inhibitors. The combinatorial targeting of EGFR and KRAS^G12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS ^G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRAS^G12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRAS^G12C inhibition in colorectal cancer. EGFR and KRAS^G12C should be concomitantly inhibited to overcome resistance to KRAS^G12C 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.

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