New research suggests that a pathway-targeted therapy could be an effective treatment for certain melanoma patients and fill an unmet clinical need for patients with advanced disease, reports MedicalXpress.
Martin McMahon, PhD, senior director of preclinical translation at Huntsman Cancer Institute and Professor of Dermatology at the t the University of Utah in the United States, evaluated the investigational drug daraxonrasib in NRAS-driven melanoma – an aggressive type of skin cancer caused by mutations in the NRAS gene.
Daraxonrasib, developed by Revolution Medicines, targets and inhibits RAS, a protein that drives cancer when altered. NRAS is a subtype of RAS that is mutated in roughly a quarter of melanoma cases.
In a phase 3 clinical trial, daraxonrasib as a treatment for metastatic pancreatic cancer doubled patients’ life expectancy.
“The remarkable success of daraxonrasib in the treatment of pancreatic cancer indicates that we are in an era where even the most recalcitrant RAS-driven cancers can be treated,” McMahon said. “Our data strongly support the potential future clinical utility of treating patients with NRAS-driven melanoma with daraxonrasib.”
He and his team evaluated the effectiveness of the RAS inhibitor in numerous preclinical models, including melanoma samples from patients. The results of the study were published in Cancer Research.
“All of our NRAS-driven models were very responsive to this RAS inhibitor. It’s actually quite rare that we see shrinkage of NRAS-driven tumours,” said Mona Foth, PhD, research scientist at Huntsman Cancer Institute and first author of the publication.
“It’s inspiring to think that these results could potentially lead to a new patient therapy that will help them overcome their disease.”
Melanoma is the deadliest form of skin cancer, and the team’s research aims to help fulfil an unmet clinical need for patients with metastatic disease. These patients usually receive immunotherapy, which harnesses a patient’s own immune system, as their first treatment. Immunotherapy has revolutionised metastatic melanoma care.
Foth said the treatment is effective in about half of melanoma patients, sometimes with deep and durable responses.
If immunotherapy fails or becomes less effective, physicians switch to targeted therapies as a second-line treatment. Targeted therapies attack oncoproteins and their effectors to kill cancer cells or slow their growth.
“Patients with other mutations like BRAF have access to clinically approved second-line treatments. But patients with NRAS-driven melanoma do not have effective targeted therapies to treat their cancer,” McMahon said.
“Daraxonrasib is a targeted therapy that may provide another path for treatment and hope for patients affected by this devastating disease.”
The team also observed that some models became resistant to the drug, as often happens in patients taking pathway-targeted therapies. Resistance to daraxonrasib was tied to mutations in the mitogen-activated protein kinase (MEK1), a protein downstream of RAS, or to loss of expression of cyclophilin A, a chaperone protein required for the inhibitory action of daraxonrasib toward RAS proteins.
“We will need to do more research to find drug combinations, based on a backbone of daraxonrasib, that will increase the depth and durability of responses in melanoma patients,” McMahon added.
He and Foth hope the drug will move into a clinical trial for patients either ineligible for immunotherapy or whose immunotherapy did not work.
Study details
Genetic drivers of sensitivity or resistance to ras(on) multiselective inhibitors in NRAS-mutated melanoma
Mona Foth, Wontak Kim, Kayla O’Toole et al.
Published in Cancer Research on 18 June 2026
Abstract
Most patients with advanced BRAF- or NRAS-driven melanoma receive first-line immunotherapy. However, if immunotherapy fails, BRAF-mutated patients receive effective second-line therapies, whereas NRAS-mutated patients lack pathway-targeted options. Recently, RAS(ON) multiselective inhibitors like RMC-7977 and the investigational agent daraxonrasib were described that inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). In this study, we found that both compounds demonstrated potent antiproliferative activity against NRAS-mutated melanoma cell lines and robust antitumor 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, 2 clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear antitumor activity in 1 patient but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in the treatment of patients with NRAS-mutated melanoma and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.
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