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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 .

EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer