Resistance, Gene by Gene

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Science  06 Dec 2013:
Vol. 342, Issue 6163, pp. 1147
DOI: 10.1126/science.342.6163.1147-b

About half of melanoma patients harbor an identical tumor-specific mutation in the BRAF gene, which encodes a protein kinase that helps drive cell growth. One of the most exciting recent advances in clinical cancer research was the discovery that this subgroup of patients respond—sometimes dramatically—to a new class of drugs targeting the MAPK pathway through which BRAF signals. Unfortunately, in most patients the melanoma recurs within a year because the tumor cells develop drug resistance. Understanding the mechanisms by which resistance arises is essential for optimizing the clinical benefits of these drugs.

Johannessen et al. used a highly systematic approach to identify candidate genes and signaling networks that contribute to resistance. After exploiting a technology that allowed them to activate each of nearly 16,000 genes individually in human melanoma cell lines containing mutant BRAF, the authors then treated the panel of cells with the drugs and monitored which cells showed altered drug sensitivity. Among the unexpected “hits” revealed by this assay were a cyclic AMP signaling network and a group of transcription factors important in melanocyte development, each suggesting potential new strategies for overcoming resistance.

Nature 10.1038/nature12688 (2013).

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