Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor
- 1Icahn School of Medicine at Mount Sinai, NY, USA
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.
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BibTeX
@misc{desaunay2026binding,
title = {{Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor}},
author = {M. Desaunay and T. Peters and E. Matenoglou and B. Baars and B. Gaire and A. Orive-Ramos and L. ren and J. P. Lyssikatos and M. R. Burkard and D. Dacus and M. J. Sale and S. A. Aaronson and F. McCormick and E. Gavathiotis and S. Gross and P. I. Poulikakos},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756774},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756774v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor
AU - M. Desaunay
AU - T. Peters
AU - E. Matenoglou
AU - B. Baars
AU - B. Gaire
AU - A. Orive-Ramos
AU - L. ren
AU - J. P. Lyssikatos
AU - M. R. Burkard
AU - D. Dacus
AU - M. J. Sale
AU - S. A. Aaronson
AU - F. McCormick
AU - E. Gavathiotis
AU - S. Gross
AU - P. I. Poulikakos
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756774
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756774v1
AB - 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.
ER -