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

Abstract

Genetic approaches have demonstrated that the p110β isoform of 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 demonstrates that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacological 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.

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

“…Because p110 isoform-selective inhibitors are available, and some of them are entering clinical trials (33), we sought to verify the isoform dependence shown in the genetic model using pharmacological inhibitors. For this study we used BYL719, a p110α-selective inhibitor currently in clinical trials for cancer patients (34), and KIN193, a p110β-selective inhibitor that effectively reduces PI3K signaling in some PTEN-deficient cancer cells (23).…”

“…Notably, ablation of p110α alone had no effect on tumor formation in this system. It has also been reported that p110β-selective inhibitors reduce AKT phosphorylation in PTEN-null human breast cancer cell lines (23). Other groups found that specific knockdown of p110β, but not p110α, resulted in downregulation of PI3K pathway signaling and inhibition of growth in both cell-based and in vivo studies of breast and prostate human Significance Aberrant activation of the PI3K pathway is a frequent event in human cancer, making PI3K an attractive target in cancer therapy.…”

“…All these studies suggested that p110β plays an important role in the tumorigenesis driven by loss of PTEN. Although considerable evidence links PTEN loss with p110β action, there are clearly human tumor cell lines featuring PTEN loss that are not dependent on p110β (23,25). Additionally, recent work has indicated that loss of PTEN in certain tissues may lead to p110α-dependent tumors in mice (26).…”

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“…64,65 Consistent with this biochemical finding, preclinical studies have shown a positive correlation between loss of PTEN and sensitivity to selective inhibitors of PI3Kβ. 66 Phase I trials of two different PI3K-selective inhibitors are currently enrolling patients (NCT01673737, NCT01458067).…”

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“…Preclinical studies have indicated that the PI3Kb isoform (containing the p110b catalytic subunit) is the critical lipid kinase that drives primarily PI3K pathway activation, cell growth, and survival in PTEN-deficient tumor cells (14)(15)(16)(17).…”