The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Alex Kim, Mark S. Cohen

Research output: Contribution to journalArticlepeer-review


Introduction: In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAFV600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAFV600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAFV600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen. Areas covered: Here we examine vemurafenib’s journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials. Expert opinion: Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAFV600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6–8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.

Original languageEnglish (US)
Pages (from-to)907-916
Number of pages10
JournalExpert Opinion on Drug Discovery
Issue number9
StatePublished - Sep 1 2016
Externally publishedYes


  • BRAF V600E
  • combination treatments
  • drug discovery
  • drug resistance
  • metastatic melanoma
  • targeted therapeutics
  • vemurafenib

ASJC Scopus subject areas

  • Drug Discovery


Dive into the research topics of 'The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma'. Together they form a unique fingerprint.

Cite this