RAC and Ruin in Melanoma

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Science  10 Aug 2012:
Vol. 337, Issue 6095, pp. 624-625
DOI: 10.1126/science.337.6095.624-d

Despite the increased use of sunscreens, the incidence of melanoma, the most lethal form of skin cancer, remains high. Tumor genome sequencing has led to new therapies targeting BRAF, a protein kinase that is activated by mutation in about 50% of melanomas and helps drive tumor growth. Because the development of resistance to BRAF inhibitors limits their long-term efficacy, there is considerable interest in identifying additional driver mutations that might form the basis of new or combination therapies.

Toward this end, Krauthammer et al. sequenced the protein-coding regions of 147 human melanoma genomes. Notably, 9% of sun-exposed melanomas harbored a point mutation in RAC1, which encodes a small GTPase (an enzyme hydrolyzing guanosine triphosphate) that regulates cytoskeletal rearrangements. Structural and functional analysis revealed that the mutation increases RAC1 binding to its downstream effectors, including PAK1 (p21-activated protein kinase), and induces melanocyte growth and migration. PAK kinases are therefore potentially druggable targets for melanoma treatment. In independent work, Hodis et al. found the same activating RAC1 mutation in 5% of their melanoma samples.

Nat. Genet. 10.1038/ng2359 (2012); Cell 150, 251 (2012).

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