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- Title
Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors.
- Authors
Clement, Emilie; Inuzuka, Hiroyuki; Nihira, Naoe T.; Wei, Wenyi; Toker, Alex
- Abstract
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.
- Subjects
PROTEIN kinase B; CELLULAR signal transduction; GENETICS of breast cancer; PHOSPHOINOSITIDE-dependent kinase-1; GENETIC mutation; GENE expression
- Publication
Science Signaling, 2018, Vol 11, Issue 521, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aao3810