Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-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 inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). Here, we found that both compounds demonstrated 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)
- Emilio Cortes-Sanchez
- Melissa M. Ronan (ORCID: https://orcid.org/0000-0003-4269-1404)
- Matthew W. VanBrocklin
- Urszula N. Wasko (ORCID: https://orcid.org/0009-0006-3029-2202)
- Montserrat Justo-Garrido (ORCID: https://orcid.org/0000-0002-1093-1031)
- Yingyun Wang (ORCID: https://orcid.org/0009-0006-6917-0245)
- Wontak Kim (ORCID: https://orcid.org/0000-0002-7388-3321)
- Siwen Hu‐Lieskovan (ORCID: https://orcid.org/0000-0001-5836-4710)
- Amanda Jiang (ORCID: https://orcid.org/0000-0002-0327-6980)
- Dekker C. Deacon (ORCID: https://orcid.org/0000-0002-4160-5730)
- Mona Foth (ORCID: https://orcid.org/0000-0001-6507-8114)
- Euan Brennan (ORCID: https://orcid.org/0009-0004-5311-1676)
- Jeffery S. Russell
- Tate Shepherd
- M. Isaac Wright
- Jennifer A. Roth
- Aparna Hegde
- Matthew G. Rees (ORCID: https://orcid.org/0000-0002-2987-7581)
- Ignacio Garrido-Laguna (ORCID: https://orcid.org/0000-0003-2273-9028)
- Sanjana Boggaram (ORCID: https://orcid.org/0009-0008-3683-0176)
- Mallika Singh (ORCID: https://orcid.org/0009-0003-0234-1589)
- Conan G. Kinsey (ORCID: https://orcid.org/0000-0001-5614-8627)
- Kayla O'Toole (ORCID: https://orcid.org/0000-0001-7627-695X)
- Phaedra Ghazi (ORCID: https://orcid.org/0000-0002-0884-9442)
- Sheri L. Holmen (ORCID: https://orcid.org/0000-0002-6411-6032)
- Jingjing Jiang (ORCID: https://orcid.org/0009-0004-2766-025X)
- Matthew Holderfield (ORCID: https://orcid.org/0000-0001-8474-3220)
- Carly Becker (ORCID: https://orcid.org/0009-0006-4318-1720)
- Brandon Murphy (ORCID: https://orcid.org/0000-0002-5692-3643)
Institutions
- Broad Institute (US)
- University of Utah (US)
- Columbia University Irving Medical Center (US)
- Huntsman Cancer Institute (US)
- Revolution Medicines (United States) (US)
- Tennessee Oncology (US)
- University of Utah Health Care (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1158/0008-5472.can-26-1313
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00