Abstract P6-21-04: Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss

Abstract

Abstract Background: PTEN functions as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to promote balanced cell proliferation, survival and differentiation. PTEN loss occurs across a variety of cancer subtypes; PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 as a single agent and in combination with standard chemotherapy and immune checkpoint inhibitors focused on tumors with loss of PTEN function. Methods: In vitro, cell proliferation assays were performed to determine the half maximal inhibitory concentration (IC50) after 3 days of treatment and to test the effects in combination with standard chemotherapy. Colony formation assays were performed to confirm efficacy of AZD8186 in PTEN-deficient cell lines. Western blot analysis was performed to assess PTEN protein expression and to evaluate effects of AZD8186 on PI3K signaling. In vivo, antitumor efficacy of AZD8186 as a single agent as well as in combination with paclitaxel and anti-PD1 was evaluated. Results: AZD8186 inhibited the cell proliferation of three of ten TNBC cell lines in vitro; PTEN loss was significantly correlated with AZD8186 sensitivity (p= 0.008). Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling with decreased expression of pAKT, pGSK3β, pPRAS40 and pS6. AZD8186 treatment of PTEN-deficient cell lines, MDA-MB-436 and MDA-MB-468, resulted in increased apoptosis. Cell proliferation assays demonstrated additive effect of the combination of paclitaxel with AZD8186. AZD8186 significantly enhanced antitumor activity of paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line-derived xenografts, with disease stabilization in the latter. In syngeneic models, AZD8186 enhanced antitumor efficacy of anti-PD1 antibodies in PTEN-deficient BP murine melanoma xenograft (p=0.0073), but not in PTEN-wildtype colon carcinoma, CT26. Conclusion: AZD8186 has single agent efficacy in PTEN-deficient triple negative breast cancer cell lines in vitro, with modest single agent efficacy in vivo. AZD8186 enhanced the antitumor efficacy of paclitaxel and of Anti-PD1 antibodies in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors. Citation Format: Owusu-Brackett N, Zhao M, Akcakanat A, Evans KW, Yuca E, Tapia C, Ileana-Dumbrava E, Janku F, Meric-Bernstam F. Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-04.