Change in Energy Pathway Enables Malignant Melanoma Cells to Survive BRAF Inhibition

A recent paper showed that BRAF (v-raf murine sarcoma viral oncogene homolog B1) -positive metastatic malignant melanoma cells survive treatment with BRAF inhibitors by increasing dependence on mitochondrial activity with concomitant change of energy production to the oxidative phosphorylation pathway.

The protein encoded by the BRAF gene plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene have been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small-cell lung carcinoma, and lung adenocarcinoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and apoptosis.

Investigators at Harvard University Medical School (Boston, MA, USA) reported in the March 7, 2013, online edition of the journal Cancer Cell that BRAF inhibition induced an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC-1alpha is a transcriptional coactivator that regulates the genes involved in energy metabolism and provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis.

The investigators showed that a target of BRAF, the melanocyte lineage factor MITF, directly regulated the expression of PGC1alpha. Melanomas with activation of the BRAF/MAPK pathway had suppressed levels of MITF and PGC1alpha and decreased oxidative metabolism. Conversely, treatment of BRAF-mutated melanomas with BRAF inhibitors rendered them addicted to oxidative phosphorylation.

"We were surprised to find that melanoma cells treated with the BRAF inhibitor vemurafenib dramatically change the way they produce energy to stay alive," said Dr. David E. Fisher, professor of dermatology at Harvard University Medical School. "While current BRAF inhibitor treatment is a major improvement – shrinking tumors in most patients and extending survival for several months – patients eventually relapse. So there is an ongoing need to improve both the magnitude and durability of these responses."

"These findings suggest that combination treatment with mitochondrial inhibitors could improve the efficacy of BRAF inhibitors in malignant melanoma," said Dr. Fisher. "Several small molecules that target mitochondrial metabolism have been identified by investigators here at Harvard and elsewhere, and laboratory investigations of specific combinations of BRAF inhibitors with mitochondrial antagonists are currently underway."

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