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 signaling; however, efficacy is often limited by suboptimal inhibition or reactivation of the pathway. To select combinations that deliver comprehensive suppression of PI3K signaling 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 antiproliferative 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. Mol Cancer Ther; 17(11); 2309-19. ©2018 AACR.
Highlights
Loss of PTEN protein expression is observed in many tumors and is associated with poorer prognosis [1,2,3,4,5], and resistance to immunotherapy [6, 7]
These data demonstrate that in cells where the combination of AZD8186 and vistusertib gave long-term growth suppression, there is greater suppression of both PI3K andmTOR signaling nodes beyond which either AZD8186 or vistusertib achieved when used as a monotherapy
Pathway biomarker analysis revealed that in sensitive cell lines the combination maintained the suppression of both PI3K and mTOR signaling and prevented recovery of active pS6 and AKT even after long-term exposure
Summary
Loss of PTEN protein expression is observed in many tumors and is associated with poorer prognosis [1,2,3,4,5], and resistance to immunotherapy [6, 7]. It has become apparent that while PTEN-null cell lines are enriched for a dependency on PI3Kb, multiple mechanisms have been associated with either feedback-mediated reactivation of signaling, or resistance to PI3Kb inhibition [19, 20]. These mechanisms include the activation of EGFR, IGFR, IR, and activation of PI3Ka or ERK signaling [21,22,23,24,25]. Inhibitors of pathways implicated in feedback reactivation or resistance were combined with the PI3Kb inhibitor AZD8186 with the aim of identifying an optimal combination for treatment of PI3Kbdependent PTEN-null tumors
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