Biomedicine

Misplacing RAS (Again)

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Science  07 Jun 2013:
Vol. 340, Issue 6137, pp. 1142-1143
DOI: 10.1126/science.340.6137.1142-d
CREDIT: G. ZIMMERMANN ET AL., NATURE 497 (30 MAY 2013) © 2013 NATURE PUBLISHING GROUP

The discovery that the mutational activation of RAS proteins drives the growth of human cancer cells catalyzed a dogged—but ultimately unsuccessful—search for drugs that inhibit RAS activity. Interest in pharmacologically targeting RAS has been revived by cancer genome studies, which revealed KRAS to be the most frequently mutated gene in the cancer types that are most common in the population and/or most refractory to therapy, such as pancreatic, lung, and colorectal cancer.

Because KRAS signaling activity is dependent on the protein's localization at the cell membrane, Zimmermann et al. investigated whether compounds that interfere with KRAS localization have anticancer activity. In a high-throughput screen, they identified small molecules that prevent KRAS from binding to PDE-δ, a protein that facilitates KRAS trafficking to the membrane. An optimized compound, deltarasin, was found to inhibit KRAS signaling and growth of KRAS-mutant human pancreatic cancer cells in vitro and in mice. Although these results are promising, the bar for deltarasin and its derivatives will be high, because previous drugs designed to disrupt KRAS membrane localization in a different way proved to be ineffective in clinical trials.

Nature 10.1038/nature12205 (2013).

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