Novel insights into the pathogenesis and treatment of NRAS mutant melanoma

Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B. Johnson, Jeffrey A. Sosman*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

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 languageEnglish (US)
Pages (from-to)281-294
Number of pages14
JournalExpert Review of Precision Medicine and Drug Development
Volume6
Issue number4
DOIs
StatePublished - 2021

Keywords

  • clinical trials
  • drug development
  • genomics
  • melanocyte
  • melanoma
  • molecular genetics
  • NRAS
  • oncology
  • pharmacology
  • precision medicine
  • targeted therapies
  • tumor biology

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology
  • Drug Discovery

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