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Functional characterization of an isoform-selective inhibitor of PI3K-p110? as a potential anticancer agent.

ABSTRACT: Genetic approaches have shown that the p110? isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110?-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 p110? inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110? 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 p110? in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110? while sparing other PI3K isoforms.We report the first functional characterization of a p110?-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 p110?-dependent PTEN-deficient human tumors.

SUBMITTER: Ni J

PROVIDER: S-EPMC3384541 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.

Ni Jing J Liu Qingsong Q Xie Shaozhen S Carlson Coby C Von Thanh T Vogel Kurt K Riddle Steve S Benes Cyril C Eck Michael M Roberts Thomas T Gray Nathanael N Zhao Jean J

Cancer discovery 20120412 5

<h4>Unlabelled</h4>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 efficac ...[more]

PMID: 22588880

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Project description:BACKGROUND:PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. METHODS:The effects of inhibiting PI3K 110? and 110? by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110? and 110? in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110? and 110? and nonspecifically influences P-gp and BCRP. RESULTS:By inhibiting the activation of the PI3K 110? and 110? catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. CONCLUSIONS:The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110? or 110? promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

Dataset Information

Functional characterization of an isoform-selective inhibitor of PI3K-p110? as a potential anticancer agent.

Publications

Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.

Similar Datasets

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