Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss
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Nicci Owusu-Brackett1, Ming Zhao2, Argun Akcakanat2, Kurt W. Evans2, Erkan Yuca2, Ecaterina Ileana Dumbrava2, Filip Janku2 and Funda Meric-Bernstam1,2,3,4
1 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3 Department of Breast Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
4 The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
|Funda Meric-Bernstam,||email:||[email protected]|
Keywords: PI3Kβ; PTEN loss; AZD8186; chemotherapy; immunotherapy
Received: October 15, 2019 Accepted: February 08, 2020 Published: March 17, 2020
Background: PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 on tumors with PTEN loss.
Results: In vitro cell viability assay and immunoblotting demonstrated that PTEN loss was significantly correlated with AZD8186 sensitivity in triple negative breast cancer (TNBC) cell lines. Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling in PTEN loss TNBC cells. AZD8186 in combination with paclitaxel, eribulin had synergistic effects on growth inhibition in PTEN loss cells. AZD8186 promoted apoptosis in PTEN loss cells which was synergized by paclitaxel. In vivo, AZD8186 had limited activity as a single agent, but enhanced antitumor activity when combined with paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line xenografts. AZD8186 significantly enhanced antitumor efficacy of anti-PD1 antibodies in the PTEN-deficient BP murine melanoma xenograft model, but not in the PTEN-wild-type CT26 xenograft model.
Methods: In vitro, cell proliferation and colony formation assays were performed to determine cell sensitivity to AZD8186. Immunoblotting was performed to assess PTEN expression and PI3K signaling activity. FACS was performed to evaluate apoptosis. In vivo, antitumor efficacy of AZD8186 and its combinations were evaluated.
Conclusions: AZD8186 has single agent efficacy in PTEN-deficient TNBC cell lines in vitro, but has limited single agent efficacy in vivo. However, AZD8186 has enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors.
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