Article

Functional Characterization of an Isoform-Selective Inhibitor of PI3K-p110β as a Potential Anticancer Agent

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02115, USA.
Cancer Discovery (Impact Factor: 19.45). 05/2012; 2(5):425-33. DOI: 10.1158/2159-8290.CD-12-0003
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ABSTRACT Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110β in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β while sparing other PI3K isoforms. SIGNIFICANCE: We report the first functional characterization of a p110β-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110β-dependent PTEN-deficient human tumors.

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    • "We speculate that this p110b-depend- ent rebound of PIP 3 requires several hours to manifest for two main reasons: (1) the time required for maximal BYL719-depen- dent release of the negative feedbacks leading to tyrosine phosphorylation of PI3K activators (e.g., ERBB3) and subsequent p110b recruitment, and (2) since p110b is a relatively inefficient enzyme in comparison to p110a (Beeton et al., 2000), PIP 3 accumulation can only be observed after sufficient time following activation. Although p110b has been identified as the primary PI3K isoform driving PI3K signaling in PTEN null tumors (Jia et al., 2008; Ni et al., 2012), the experiments in this study suggest that p110b activation also promotes the viability of p110a-driven breast cancers following treatment with p110a-s- pecific inhibitors. In vivo, p110a inhibition blocked tumor growth but did not induce tumor shrinkage in either the HER2-amplified or PIK3CA mutant xenograft models. "
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