Combined inhibition of PI3Kβ and mTOR inhibits growth of PTEN null tumours.

Abstract

Loss of the tumor suppressor PTEN confers a tumor cell dependency on the PI3Kβ isoform. Achieving maximal inhibition of tumor growth through PI3K pathway inhibition requires sustained inhibition of PI3K signalling, however efficacy is often limited by sub-optimal inhibition or reactivation of the pathway. To select combinations that deliver comprehensive suppression of PI3K signalling in PTEN null tumors, the PI3Kβ inhibitor AZD8186 was combined with inhibitors of kinases implicated in pathway reactivation in an extended cell proliferation assay. Inhibiting PI3Kβ and mTOR gave the most effective anti-proliferative effects across a panel of PTEN null tumor cell lines. The combination of AZD8186 and the mTOR inhibitor vistusertib was also effective in vivo controlling growth of PTEN null tumor models of TNBC, prostate and renal cancers. In vitro the combination resulted in increased suppression of pNDRG1, p4EBP1 as well as HMGCS1 with reduced pNDRG1 and p4EBP1 more closely associated with effective suppression of proliferation. In vivo biomarker analysis revealed that the monotherapy and combination treatment consistently reduced similar biomarkers, while combination increased nuclear translocation of the transcription factor FOXO3 and reduction in glucose uptake. These data suggest that combining the PI3Kβ inhibitor AZD8186 and vistusertib has potential to be an effective combination treatment for PTEN null tumors.