The response of cancers to BRAF inhibition underscores the importance of cancer systems biology.
The BRAF inhibitor vemurafenib has become an important treatment option for melanoma patients, the majority of whom have a BRAF(V600E) mutation driving their malignancy. However, this same agent does not generally benefit colon cancer patients who have the BRAF(V600E) mutation. Recent work suggests that BRAF(V600E) inhibition by vemurafenib results in decreased negative feedback to the epidermal growth factor receptor (EGFR) pathway and that the different clinical responses are due to differences in the amount of EGFR present in these two cancers. The experimental work that identified the feedback signaling was an elegant mix of functional genomic approaches and focused, hypothesis-driven cellular and molecular biology. The results of these studies suggest that combined treatment of BRAF(V600E)-driven colon cancers with both vemurafenib and EGFR inhibitors is worth clinical evaluation.
Clinical Translational Research Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA. estites@tgen.org
Edward C
EC
Stites
D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy*; D008954:Models, Biological; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology; D049490:Systems Biology / Q000379:methods; D000077484:Vemurafenib
D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf