EML4−ALK Mediates Resistance to KRASG12C Inhibition and Induces an Oncogenic Dependency by Rewiring Signaling through the Wild-Type RAS Pathway

Abstract KRAS mutations are common oncogenic drivers in human cancers, with the KRASG12C variant being a key target in lung adenocarcinoma. Despite the FDA approval of KRASG12C-selective inhibitors, their clinical efficacy has been limited, as evidenced by trials showing modest response rates and resistance development through the selection of acquired genomic alterations. Our study explores the mechanisms underlying acquired EML4–ALK fusion in KRASG12C-driven tumors developing resistance to KRASG12C inhibitors and potential therapeutic strategies to overcome it. Our findings reveal that combined ALK/KRASG12C inhibition is an effective therapeutic approach in this context. Moreover, we observed that KRASG12C/EML4–ALK tumor cells kept under constant pressure with KRASG12C inhibitors exhibit sensitivity to single-agent ALK inhibitors, suggesting a potential for rationally designed sequential treatments. Mechanistically, EML4–ALK bypasses KRASG12C inhibition by activating wild-type RAS, highlighting an additional therapeutic opportunity for multiselective RAS inhibitors under clinical investigation. Significance: Acquired EML4–ALK fusions confer resistance to KRAS inhibition in KRASG12C-driven lung adenocarcinoma. By rewiring the oncogenic signaling under inhibitor pressure, EML4–ALK creates a new oncogenic dependency that can be exploited for more effective therapeutic strategies.