About

Martin McMahon, PhD, is the Cumming-Presidential Chair of Cancer Biology and Senior Director for Preclinical Translation at the Spencer Fox Eccles School of Medicine. He earned his PhD in 1985 from King’s College University of London for studies on interferon action, conducted at the ICRF in London and Stanford University. Mentored by Mike Bishop at UC San Francisco, he completed postdoctoral training working on oncoprotein kinases such as v-SRC, v-ERBB, and RAF. In 1991, he established an independent research lab at the DNAX Research Institute focusing on RAF protein kinases. He joined UCSF in 1998, serving as the Efim Guzik Distinguished Professor of Cancer Biology until 2015, after which he joined the University of Utah’s Huntsman Cancer Institute. Dr. McMahon’s research centers on the mechanisms underlying the development of metastatic melanoma and lung cancer driven by mutationally-activated RAS or RAF oncoproteins. His laboratory works with cultured human cancer-derived cells, patient-derived xenograft models, and genetically engineered mouse models to demonstrate the value of these systems in designing and evaluating diagnostic, prognostic, and therapeutic tools for cancer treatment. Throughout his career, he has contributed significantly to the field, serving as President of the Society for Melanoma Research, Chair of the NCI Board of Scientific Counsellors, and holding leadership roles in various philanthropic and government agencies. His work has been recognized with awards such as the American Skin Association Leadership in Melanoma Award in 2017 and the Society for Melanoma Research Lifetime Achievement Award in 2022. In addition to his research, Dr. McMahon is actively involved in education and mentorship, having mentored over 50 students and fellows, and participating in graduate programs in Molecular Biology and Biological Chemistry at the University of Utah. He teaches courses focused on cancer biochemistry and biology, and in 2025, he will serve as a course organizer for a cancer-focused elective on oncogene addiction in cancer. His service includes participation in numerous NIH study sections, editorial boards, and organizing international conferences, reflecting his prominent role in the cancer research community.

Research topics

• Cancer research
• Biology
• Medicine
• Chemistry
• Cell biology
• Internal medicine
• Biotechnology
• Bioinformatics
• Computational biology
• Pharmacology
• Pathology
• Genetics

Selected publications

• Identification and characterization of BRAF⇔TP53 interactions in melanoma

  Cell Reports · 2026-03-20

  articleOpen accessSenior author

  functionally inactivates TP53 and reveal a mechanism by which melanoma bypasses TP53-mediated tumor suppression without requiring genetic alteration.

  PublisherDOI

• Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance

  Oncogene · 2026-04-28

  articleOpen access

  Abstract The intrinsic ability of cancer cells to evade death underpins tumorigenesis, progression, metastasis, and the survival of drug-tolerant persister (DTP) cells. Herein, we discovered that the small GTPase ARF6 plays a central role in tumor survival by fortifying RAF oncoprotein levels. ARF6 activation was sufficient to increase BRAF V600E , ARAF, and CRAF proteins through a post-transcriptional mechanism, while sustained inhibition of ARF6 eventually led to decay. In a genetically engineered model of aggressive melanoma, tumor-specific Arf6 deletion attenuated BRAF V600E protein expression and MAPK signaling and prevented rapid tumor progression. In human melanoma cells, pharmacologic inhibitors of BRAF V600E uniformly induced swift activation of ARF6, driving a positive feedback loop that restored MAPK-driven anti-apoptotic signaling and supported drug-tolerant survival and growth. Furthermore, in patient-derived melanoma xenografts with innate or clinically acquired resistance to MAPK inhibitors, ARF6 silencing alone significantly suppressed tumor growth in vivo. When combined with BRAF and MEK targeted therapy in vitro, inhibition of ARF6 markedly reduced survival and drug-tolerant growth. Collectively, these findings reveal a previously unknown mechanism of maintaining BRAF V600E protein expression that preserves the MAPK pathway during targeted therapy. This ARF6-dependent mechanism may be exploited in BRAF V600E driven cancers as a therapeutic vulnerability.

  PublisherOA PDFDOI

• Safeguarding Competencies for Designated Officers and Professionals Working in Adult Safeguarding: A Scoping Review Protocol

  Open MIND · 2026-01-01

  otherOpen access

  This scoping review will map and synthesise national and international evidence on safeguarding competencies for Designated Officers and professionals with safeguarding responsibilities in adult safeguarding contexts. The review will examine how safeguarding competencies are defined and operationalised, including competency domains, training requirements, and governance frameworks. Findings will identify key characteristics, areas of convergence and divergence, and existing benchmarks to inform the development of safeguarding competencies within the Irish health and social care context as part of an HSE-funded national study.

  PublisherDOI

• Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in NRAS-Mutated Melanoma

  Cancer Research · 2026-05-22

  articleSenior author

  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.

  PublisherDOI

• Healthcare Utilisation in Ageing Adults With Intellectual Disability: Longitudinal Evidence From Five Waves of <scp>IDS</scp> ‐ <scp>TILDA</scp>

  Journal of Applied Research in Intellectual Disabilities · 2026-04-28

  articleOpen access1st authorCorresponding

  BACKGROUND: Adults with intellectual disability are living longer and ageing with more illness. This impacts healthcare utilisation. Yet little is known about how healthcare utilisation changes over time as this population ages. METHODS: Five waves of longitudinal data of people ≥ 40 years with intellectual disability from 2009 to 2023 were analysed. Generalised linear multilevel models examined associations between sociodemographic characteristics and multimorbidity with patterns of General Practitioner (GP), outpatient and emergency department use. RESULTS: GP use was consistently high across all waves. Outpatient use increased as people aged, while emergency department use was associated with age greater than 65, multimorbidity and conditions such as neurological, joint, gastrointestinal, endocrine and heart disease. Residence was a significant factor influencing healthcare utilisation. CONCLUSION: Our findings demonstrate that multimorbidity, residence and age were associated with healthcare utilisation. These are important insights to help support the planning of accessible and preventative health services for this population.

  PublisherDOI

• Abstract IA006: Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi- Selective Inhibitors in NRAS-Mutated Melanoma

  Cancer Research · 2026-03-05

  articleSenior author

  Abstract 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. Citation Format: Mona Foth, Wontak Kim, Kayla O'Toole, Brandon Murphy, Montserrat Justo-Garrido, Sanjana Boggaram, Phaedra Ghazi, Euan Brennan, Isaac Wright, Tate Shepherd, Emilio Cortes-Sanchez, Yingyun Wang, Jennifer Roth, Matthew Rees, Melissa Ronan, Jingjing Jiang, Ursula Wasko, Amanda Jiang, Carly Becker, Dekker Deacon, Siwen Hu-Lieskovan, Conan Kinsey, Jeffery Russell, Aparna Hegde, Ignacio Garrido-Laguna, Matthew Holderfield, Mallika Singh, Martin McMahon. Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi- Selective Inhibitors in NRAS-Mutated Melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr IA006.

  PublisherDOI

• Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance

  Research Square · 2025-08-27

  preprintOpen access
  PublisherOA PDFDOI

• Abstract 4143: Analyzing BRAFV600E signaling complexes to better understand BRAF driven melanoma

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract In approximately 8% of all cancers, mutational activation of BRAF is an oncogenic driver, with a particular prevalence in lung cancer, thyroid cancer, and melanoma. Mutations in BRAF account for about 50% of the cutaneous melanoma cases in patients. The most common mutational alteration is the BRAFT1799A encoding the BRAFV600E oncoprotein kinase. Combined inhibition of BRAFV600E and MEK 1/2 has been approved to treat BRAFV600E-driven melanoma and lung cancer. There are several mechanisms of resistance to inhibitors of BRAFV600E signaling, with one of the most intriguing being the emergence of tumors expressing p61-BRAFV600E that is encoded by a variant mRNA that is aberrantly spliced to remove exons 4-8. Consequently, p61-BRAFV600E is missing amino acid sequences that promote association with RAS.GTP (RBD) and the cysteine rich domain (CRD). Moreover, while full-length BRAFV600E is widely considered to signal as a monomer, p61-BRAFV600E is thought to require dimerization for activation. Here, we use gel-filtration chromatography and immunoblotting to show that both forms of BRAFV600E are detected in a large molecular weight complex of 450-500 kDa. However, p61-BRAFV600E containing complexes are smaller than those with full-length BRAFV600E, which may reflect the difference in size of the BRAFV600E proteins or subtle differences in the signaling complexes. Interestingly, the addition of a BRAFV600E inhibitor, vemurafenib, shifted the elution of complexes with full-length BRAFV600E into lower molecular weight fractions. In addition, we have utilized the proximity labeling technique, TurboID, to uncover more of the BRAF interactome. Citation Format: Adamaris M. Martinez, Kayla T. O'Toole, Martin McMahon. Analyzing BRAFV600E signaling complexes to better understand BRAF driven melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4143.

  PublisherDOI

• Author Correction: Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers

  Nature Medicine · 2025-04-25 · 1 citations

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi-Selective Inhibitors in <i>NRAS</i> -Mutated Melanoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-21

  articleOpen accessSenior authorCorresponding

  ABSTRACT 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. SIGNIFICANCE There are no pathway-targeted therapies for patients with NRAS -mutated melanoma. Here we demonstrate that direct pharmacological inhibition of RAS[GTP] with RMC-7977 or daraxonrasib (RMC-6236) has profound inhibitory effects in preclinical models of NRAS -mutated melanoma. Furthermore, we identify mechanisms of resistance to RMC-7977 through mutational inactivation of CYPA or mutational activation of MEK1.

  PublisherOA PDFDOI

Recent grants

• Utah Population Database (UPDB)

  NIH · $39.0M · 1997–2027

• NIH Grant R01CA108972

  NIH · $1.4M · 2010

• Studying the initiation, progression and therapy of lung cancer in mouse models

  NIH · $5.3M · 2009–2027

• Targeting Oncogenic NRAS, BRAF plus PI3'-Kinase Signaling for Melanoma Therapy

  NIH · $2.9M · 2013–2029

Frequent coauthors

• David Dankort

  152 shared

• Christy L. Trejo

  115 shared

• Conan G. Kinsey

  University of Utah

  108 shared

• Michael T. Scherzer

  94 shared

• Wayne A. Phillips

  University of Melbourne

  82 shared

• Christopher M. Stehn

  80 shared

• Shon Green

  78 shared

• Sheri L. Holmen

  Huntsman Cancer Institute

  76 shared

Education

• Ph.D., Biochemical Regulatory Mechanisms

  Imperial Cancer Research Fund

  1985

• Ph.D., Biochemistry

  King's College London

  1985

• B.Sc. (Hons, 1st class), Biochemistry

  University of Glasgow

  1981

Awards & honors

• Leadership in Melanoma Award (2017)
• Society for Melanoma Research Lifetime Achievement Award (20…