Abstract
Introduction: NRAS was the first mutated oncogene identified in melanoma and is currently the second most common driver mutation in this malignancy. For patients with NRASmutant advanced stage melanoma refractory to immunotherapy or with contraindications to immune-based regimens, there are few therapeutic options including low-efficacy chemotherapy regimens and binimetinib monotherapy. Here, we review recent advances in preclinical studies of molecular targets for NRAS mutant melanoma as well as the failures and successes of early-phase clinical trials. While there are no targeted therapies for NRAS-driven melanoma, there is great promise in approaches combining MEK inhibition with inhibitors of the focal adhesion kinase (FAK), inhibitors of autophagy pathways, and pan-RAF inhibitors. Areas Covered: This review surveys new developments in all aspects of disease pathogenesis and potential treatment–including those that have failed, stalled, or progressed through various phases of preclinical and clinical development. Expert Opinion: There are no currently approved targeted therapies for BRAF wild-type melanoma patients harboring NRAS driver mutations though an array of agents are in early phase clinical trials. The diverse strategies taken exploit combined MAP kinase signaling blockade with the inhibition of cell cycle mediators, inhibition of the autophagy pathway, and alteration of kinases involved in actin cytoskeleton signaling. Future advances of developmental therapeutics into late stage trials may yield new options beyond immunotherapy for patients with advanced stage disease and NRAS mutation status.
Original language | English (US) |
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Pages (from-to) | 281-294 |
Number of pages | 14 |
Journal | Expert Review of Precision Medicine and Drug Development |
Volume | 6 |
Issue number | 4 |
DOIs | |
State | Published - 2021 |
Funding
DB Johnson is funded by NIH/NCI 1R01CA227481, the James C. Bradford Jr. Melanoma Fund, and receives industry research-related funding from BMS and Incyte. JA Sosman is funded by the Melanoma Research Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R61AR076824-01), National Cancer Institute (1R01CA250101-01; 410013075//2UM1CA186644-06; 5R01CA222963-03; 5R01CA208354-02) and reports industry research-related funding from NeoImmuneTech, Inc., Amphivena Therapeutics, Inc., Bristol-Myers Squibb Company, Corvus Pharmaceuticals, Inc., Covance Inc., Nektar Therapeutics, Calithera Biosciences, Inc., Hoosier Cancer Research Network, Inc., DrugDev Inc., Merck Sharp & Dohme Corporation. KEB is funded by K12CA090625 and reports industry research-related funding from BMS-IASLC-LCFA through a young investigator award. No other authors report any relevant research-related funding sources. DB Johnson serves on advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst, Jansen, Iovance, Incyte, Merck, Novartis, and Oncosec, and receives research funding from Bristol Myers Squibb and Incyte. JA Sosman serves on advisory Boards for Bristol Myers Squibb, Incyte, Genentech, and Curis. KEB has consulted for Aravive and Exelexis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Keywords
- NRAS
- clinical trials
- drug development
- genomics
- melanocyte
- melanoma
- molecular genetics
- oncology
- pharmacology
- precision medicine
- targeted therapies
- tumor biology
ASJC Scopus subject areas
- Drug Discovery
- Genetics
- Molecular Medicine
- Pharmacology