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

Nicci Owusu-Brackett,Erkan Yuca,Ecaterina Ileana Dumbrava,Ming Zhao,Kurt W Evans,Argun Akcakanat,Funda Meric-Bernstam,Filip Janku

doi:10.18632/oncotarget.27503

Nicci Owusu-Brackett, Erkan Yuca + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.27503

Copy DOI

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 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.

Highlights

Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell [1]
Immunoblotting showed that all these triple negative breast cancers (TNBC) cell lines, including the Phosphatase and tensin homolog (PTEN) null cell lines, expressed PI3Kβ at various levels (Figure 1A)
Western blot showed that PTEN expression is lost in three cell lines, BT-549, MDA-MB-468, and MDA-MB-436, while other seven cell lines expressed PTEN at various levels (Figure 1A)

Summary

Introduction

Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is an important regulator of many physiological cellular processes that promote differentiation, proliferation and survival of a normal cell [1]. Loss of copy number, epigenetic silencing and downregulation of PTEN protein by miRNA can result in PTEN function inactivation, leading to activation of PI3K/ AKT/mTOR pathway, which subsequently increases tumor growth, invasion and metastasis across a diverse set of solid tumors including breast, endometrial, prostate, renal cell, hepatocellular, glioblastoma and colorectal cancers [5, 6]. Wee et al demonstrated that PTEN-deficient tumors are dependent on PI3Kβ catalytic isoform activity [11]. In vitro, they revealed significant growth inhibition of PTEN-deficient tumors by depleting PIK3CB which encodes PI3Kβ, while no such growth inhibition effect was shown in corresponding PTEN-deficient tumors with downregulation of PIK3CA or PIK3CD encoding PI3Kα and PI3Kδ, respectively. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 on tumors with PTEN loss

Methods

Results

Conclusion