Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma

About 25% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.