Research ArticleCancer therapy

Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors

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Sci. Signal.  13 Mar 2018:
Vol. 11, Issue 521, eaao3810
DOI: 10.1126/scisignal.aao3810

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Skp’ing down a path of resistance

Predicting how a tumor can adapt to a drug may help identify the patients most likely to respond as well as strategies to avoid resistance. Activation of the kinase PI3K drives the growth of many cancers, but resistance to targeted PI3K pathway inhibitors is common. Clement et al. analyzed triple-negative breast cancer cell lines and found that high abundance of the ubiquitin ligase Skp2 is a predictive biomarker of PI3K inhibitor resistance. Using cultured cells and in tumors in mice, they found that Skp2 ubiquitylated the PI3K pathway kinase AKT, which promoted its activation independently of PI3K, such that PI3K inhibitors were ineffective at suppressing growth. Thus, a Skp2-targeted combination therapy may prevent PI3K inhibitor resistance in some patients with this aggressive type of breast cancer.