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