The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma.
BACKGROUND
In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAF(V600) 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 BRAF(V600) mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAF(V600) inhibitor, vemurafenib, was identified initially through a large-scale drug screen.


METHODS
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.


CONCLUSIONS
Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAF(V600) 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.
a Department of Surgery , University of Michigan , Ann Arbor , MI , USA.
Alex
A
Kim
a Department of Surgery , University of Michigan , Ann Arbor , MI , USA.
Mark S
MS
Cohen
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF V600E; combination treatments; drug discovery; drug resistance; metastatic melanoma; targeted therapeutics; vemurafenib