Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma [Mouse_iAKP_Abr24]

Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms, in CCA preclinical models and patients. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and in immunocompetent allograft models.

Consistently, we describe responses to the RAS(ON) multi-selective inhibitor daraxonrasib in two KRASG12X patients with advanced CCA. RAS-GTP inhibition also potentiates the activity of the current standard-of-care CCA therapy to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that both intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on reconstitution of RAS signalling.