Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor.

Authors

Mathieu Desaunay, Tara L Peters, Evangelia Matenoglou, Beau Baars, Bijaya Gaire, Ana Orive-Ramos, Li Ren, Joseph P Lyssikatos, Michael R Burkard, Dalton Dacus, Matthew J Sale, Stuart A Aaronson, Frank McCormick, Evripidis Gavathiotis, Stefan D Gross, Poulikos I Poulikakos

Published in

bioRxiv : the preprint server for biology. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

Therapeutic inhibition of the RAS/MAPK cascade, an oncogenic driver in over one-third of human cancers, has been limited by a core trade-off: effective pathway blockade in tumors versus dose-limiting toxicity in normal tissues. Although Type 1.5 RAF inhibitors successfully mitigated this trade-off in BRAF-monomer-driven tumors, an equivalent strategy has been lacking for RAF-dimer- driven cancers, including those with RAS mutations. Here, we characterize ELV-3111, a next-generation, potent, and selective Type 1 RAF inhibitor that overcomes this limitation via a distinct mechanism of action. ELV-3111 induces paradoxical MAPK hyperactivation in normal tissues by binding RAF and promoting the active conformation (priming) followed by rapid dissociation (fast off-rate), a biochemical feature that spares RAS-mutant tumors, where RAF is already primed. In these and other RAF dimer-driven tumor models, ELV-3111 achieves potent and selective MAPK and growth suppression. When combined with a MEK inhibitor, ELV-3111 enables complementary pharmacology: additive inhibition in tumors and compensatory effects in normal tissues. The combination produced durable regressions across RAS-mutant and BRAF-mutant models, including a RAS-mutant model refractory to current therapies, while maintaining favorable tolerability. Thus, we uncover a generalizable mechanism that enables Type 1 RAF inhibitor plus MEK inhibitor combinations to achieve tumor-selective MAPK suppression, with the potential to inform targeted therapy design.

PMID:
42926471
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.

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