Beating BRAF resistance

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Science Translational Medicine  15 Apr 2015:
Vol. 7, Issue 283, pp. 283ec62
DOI: 10.1126/scitranslmed.aab2766

A paragon of personalized medicine, the V600E gain-of-function mutation in the BRAF gene drives development of diverse types of human cancer, including 50% of malignant melanomas and 10% of colorectal cancers. Targeted BRAF inhibitors produce remarkable remission rates in patients suffering from otherwise incurable metastatic melanoma, but the development of drug resistance renders treatment responses transient. Further, nonmelanoma tumors such as colorectal cancer carrying the BRAF V600E mutation are generally intrinsically resistant to monotherapy with BRAF inhibitors. Finding a key to unlocking this intrinsic resistance is a crucial quest in extending the spectrum of tumors sensitive to BRAF inhibition. Now, Ahronian et al. take an important step toward overcoming colorectal-tumor resistance to BRAF inhibitors.

The authors studied—both before treatment and after the development of resistance to BRAF inhibitors—three colorectal cancer patients who responded to BRAF inhibitors when administered in combination with other targeted therapeutic agents. A combination of whole-exome and RNA sequencing of tumors revealed that resistance development could be explained by the acquisition of new mutations after treatment. These mutations were diverse and included genomic amplification of BRAF and the KRAS oncogene and activating point mutations in the BRAF-signaling related ARAF and MEK genes. In spite of the diversity of resistance mechanisms, these mutations all occurred within the BRAF signaling pathway. Remarkably, the investigators unearthed an overarching Achilles’ heel of these diverse resistance mechanisms: In vitro inhibition of the ERK protein, a distal node within the BRAF signaling cascade, neutralized resistance to BRAF inhibitors in the case of every mutation. Availability of ERK inhibitors for clinical use lies on the horizon, as these are currently being tested in clinical trials.

Although this study is small in size, it provides fundamental insights into the mechanisms underlying BRAF-inhibitor resistance in patients suffering from colorectal cancer. Further, Ahronian and colleagues provide the level of detail required to understand personalized medicine at the patient level. Tumors will need to be reevaluated, and treatments retailored, as a patient’s disease changes.

L. G. Ahronian et al., Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 5, 358–367 (2015). [Abstract]

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