Research ArticleCancer therapy

Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors

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

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.


The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways. We found a previously unknown resistance mechanism to PI3K pathway inhibition that results in AKT rebound activation. In a subset of triple-negative breast cancer cell lines, treatment with a PI3K inhibitor or depletion of PIK3CA expression ultimately promoted AKT reactivation in a manner dependent on the E3 ubiquitin ligase Skp2, the kinases IGF-1R (insulin-like growth factor 1 receptor) and PDK-1 (phosphoinositide-dependent kinase-1), and the cell growth and metabolism-regulating complex mTORC2 (mechanistic target of rapamycin complex 2), but was independent of PI3K activity or PIP3 production. Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice. These findings reveal a ubiquitin signaling feedback mechanism by which PI3K inhibitor resistance may emerge in aggressive breast cancer cells.

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