Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3K?/?/? Inhibitor BAY1082439.

ABSTRACT: Targeting the PI3K pathway is a promising strategy for treating prostate cancers with PTEN-loss. However, current anti-PI3K therapies fail to show long lasting in vivo effects. We find that not only the PI3K?- and PI3k?-isoforms, but also PI3K?, are associated with the epithelial-mesenchymal transition (EMT), a critical process distinguishing indolent from aggressive prostate cancer. This suggests that cotargeting PI3K?/?/? could preempt the rebound activation of the parallel pathways induced by ?- or ?-isoform-selective inhibitor and prevent EMT. Indeed, BAY1082439, a new selective PI3K?/?/? inhibitor, is highly effective in vivo in inhibiting Pten-null prostate cancer growth and preventing EMT in the mutant Pten/Kras metastatic model. The anti-PI3K? property of BAY1082439 further blocks B-cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3K?/?/? inhibitor. Mol Cancer Ther; 17(10); 2091-9. ©2018 AACR.

SUBMITTER: Zou Y 

PROVIDER: S-EPMC6168338 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature