2. Academic Validation
  3. Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439

Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439

  • Mol Cancer Ther. 2018 Oct;17(10):2091-2099. doi: 10.1158/1535-7163.MCT-18-0038.
Yongkang Zou  # 1,  Zhi Qi  # 1,  Weilong Guo 1,  Liuzhen Zhang 1,  Marcus Ruscetti 2,  Tanu Shenoy 2,  Ningshu Liu 3,  Hong Wu 4 2
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences and Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China.
  • 2 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.
  • 3 Bayer AG, Drug Discovery TRG Oncology, Berlin, Germany.
  • 4 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences and Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China. hongwu@pku.edu.cn.
  • # Contributed equally.
PMID: 30045927 DOI: 10.1158/1535-7163.MCT-18-0038
Abstract

Targeting the PI3K pathway is a promising strategy for treating prostate cancers with PTEN-loss. However, current anti-PI3K therapies fail to show long lasting in vivo effects. We find that not only the PI3Kα- and PI3kβ-isoforms, but also PI3Kδ, are associated with the epithelial-mesenchymal transition (EMT), a critical process distinguishing indolent from aggressive prostate Cancer. This suggests that cotargeting PI3Kα/β/δ could preempt the rebound activation of the parallel pathways induced by α- or β-isoform-selective inhibitor and prevent EMT. Indeed, BAY1082439, a new selective PI3Kα/β/δ inhibitor, is highly effective in vivo in inhibiting Pten-null prostate Cancer growth and preventing EMT in the mutant PTEN/Kras metastatic model. The anti-PI3Kδ property of BAY1082439 further blocks B-cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate Cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor. Mol Cancer Ther; 17(10); 2091-9. ©2018 AACR.

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