2026/06/22 by Pietro Scaparone, Alessia Mira, Taek-Chin Cheong +19 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Lung Cancer Treatments and Mutations #Microtubule and mitosis dynamics #Protein Kinase Regulation and GTPase Signaling
paper · doi:10.1158/2159-8290.cd-25-0477
openalex publication_date 2026/06/22 · openalex created_date 2026/06/23 · openalex updated_date 2026/07/22
KRAS mutations are common oncogenic drivers in human cancers, with the KRASG12C variant being a key target in lung adenocarcinoma (LUAD). 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 multi-selective RAS inhibitors under clinical investigation.