Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in <i>NRAS</i> -Mutated Melanoma
Most patients with advanced BRAF or NRAS-driven melanoma receive front-line immunotherapy. However, if immunotherapy fails, BRAF-mutated patients have effective second-line therapies, whereas NRAS-mutated patients lack pathway-targeted options. Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that, in partnership with cyclophilin-A (CYPA), inhibit RAS[GTP] signaling. Both compounds demonstrate potent anti-proliferative activity against NRAS-mutated melanoma cell lines and robust anti-tumor activity against preclinical melanoma models. However, in preclinical models, resistance to RMC-7977 monotherapy arose through mutations in Ppia (encoding CYPA) or Map2k1 (encoding MEK1). Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.
Authors
- Martin McMahon (ORCID: https://orcid.org/0000-0003-2812-1042)
- Phaedra C. Ghazi (ORCID: https://orcid.org/0000-0002-0884-9442)
- Emilio Cortes Sanchez
- Melissa M. Ronan (ORCID: https://orcid.org/0000-0003-4269-1404)
- Urszula N. Wasko (ORCID: https://orcid.org/0009-0006-3029-2202)
- Matthew Holderfield (ORCID: https://orcid.org/0000-0001-8474-3220)
- Montserrat Justo-Garrido (ORCID: https://orcid.org/0000-0002-1093-1031)
- Yingyun Wang (ORCID: https://orcid.org/0009-0006-6917-0245)
- Aparna Hegde (ORCID: https://orcid.org/0000-0001-6616-4882)
- Kayla T. O'Toole
- Jennifer A. Roth (ORCID: https://orcid.org/0000-0002-5117-5586)
- Mallika Singh (ORCID: https://orcid.org/0009-0003-0234-1589)
- Wontak Kim (ORCID: https://orcid.org/0000-0002-7388-3321)
- Matthew G. Rees (ORCID: https://orcid.org/0000-0002-2987-7581)
- Dekker C. Deacon (ORCID: https://orcid.org/0000-0002-4160-5730)
- Conan G. Kinsey (ORCID: https://orcid.org/0000-0001-5614-8627)
- Mona Foth (ORCID: https://orcid.org/0000-0001-6507-8114)
- Euan Brennan (ORCID: https://orcid.org/0009-0004-5311-1676)
- Sanjana Srinivas Boggaram
- Jeffery Russel
- Tate Shepherd
- Brandon Murphy
- Ignacio Garrido-Laguna
- Siwen Hu-Lieskovan
- Amanda Jiang
- M. Isaac Wright
- Carly Becker
- Jingjing Jiang
Institutions
- Broad Institute (US)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Revolution Medicines (United States) (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-21
- DOI
- https://doi.org/10.64898/2025.12.18.695203
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Eli Lilly and Company
- Revolution Medicines