Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer

Xueliang Gao, Yubao Wang, Caroline F. Ribeiro, Cherubin Manokaran, Hyeyoun Chang, Thanh Von, Silvia Rodrigues, Onur Cizmecioglu, Shidong Jia, Manav Korpal, Joshua M. Korn, Zhigang Wang, Fabienne Schmit, Lan Jiang, Raymond Pagliarini, Yi Yang, Isha Sethi, Sabina Signoretti, Guo Cheng Yuan, Massimo LodaJean J. Zhao, Thomas M. Roberts

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110β inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110β/RAC/PAK1 and β-catenin pathways in CRPC, we found that combining p110β with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110β activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC. Implications: This work establishes p110β as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.

Original languageEnglish
Pages (from-to)673-685
Number of pages13
JournalMolecular Cancer Research
Volume20
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

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