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Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

Leroy, Cedric and Ramos, Pedro and Cornille, Karen and Fritsch, Christine and Bonenfant, Debora and Voshol, Johannes and Bentires-Alj, Mohamed (2016) Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition. Breast Cancer Research.

Abstract

The PI3K pathway is hyperactivated in many cancers, including 70% of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected. In order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines and assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics. We found an increase in IGF1R, IRS1/IRS2 and p85 phosphorylation in the resistant lines. Co-immunoprecipitation experiments identified an IGF1R/IRS/p85/p110β complex that causes the activation of AKT/mTOR/S6K and stifles the effects of BYL719. Pharmacological inhibition of members of this complex reduced mTOR/S6K activation and restored sensitivity to BYL719. Our study demonstrates that p110β confers resistance to BYL719 in PIK3CA mutant breast cancers. This provides a rationale for the combined targeting of p110α with IGF1R or p110β in patients with breast tumors harboring PIK3CA mutations.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/26360

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