Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss

Abstract

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 PTENdeficient 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.

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

“…A phase I clinical trial (NCT01884285) is also studying the PI3KCB/PI3KCD inhibitor AZD8186 in patients with TNBC and known PTEN-deficient/-mutated or PIK3CB-mutated/-amplified advanced tumors and in combination with abiraterone acetate or AZD2014, an mTOR inhibitor [ 104 ]. AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro, but has limited single-agent efficacy in vivo [ 105 ]. However, AZD8186 showed enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo [ 105 ].…”

“…AZD8186 has single-agent efficacy in PTEN-deficient TNBC cell lines in vitro, but has limited single-agent efficacy in vivo [ 105 ]. However, AZD8186 showed enhanced efficacy when combined with paclitaxel and anti-PD1 in vivo [ 105 ]. Further study is needed to determine the optimal combination therapies for PTEN-deficient breast cancer.…”

Investigational Drug Treatments for Triple-Negative Breast Cancer

“…In 2020, Owusu-Brackett et al reported a study, in which in vitro cell viability assay and immunoblotting indicated that PTEN loss was related to AZD8186 sensitivity in TNBC [ 29 ]. Colony formation assay was also studied and confirmed the sensitivity of PTEN deficient cell lines to AZD8186.…”

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

“…Specifically, AKT inhibition can led to a favorable immune profile in the breast tumor microenvironment, including an increased density of CD3+CD8+ cells and better expression of interferon genes, providing a rationale for using AKT inhibition plus immunotherapy combination ( Marks et al, 2020 ). Correspondingly, the PI3Kβ inhibitor AZD8186 enhanced anticancer efficacy by combining with anti-PD1 Ab in PTEN-deficient xenografts ( Owusu-Brackett et al, 2020 ). Combining nanoscale PI3K-targeting supramolecular therapeutics with anti-PD-L1/PD-1 Ab exhibited a synergetic anticancer effect in breast cancer in vivo ( Kulkarni et al, 2016 ).…”