Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth

Pearson, Helen B. ORCID: https://orcid.org/0000-0002-3284-0843, Li, Jason, Meniel, Valerie S., Fennell, Christina M., Waring, Paul, Montgomery, Karen G., Rebello, Richard J., Macpherson, Arthi A., Koushyar, Sarah, Furic, Luc, Cullinane, Carleen, Clarkson, Richard W. ORCID: https://orcid.org/0000-0001-7389-8673, Smalley, Matthew J. ORCID: https://orcid.org/0000-0001-9540-1146, Simpson, Kaylene J., Phesse, Toby J. ORCID: https://orcid.org/0000-0001-9568-4916, Shepherd, Peter R., Humbert, Patrick O., Sansom, Owen J. and Phillips, Wayne A. 2018. Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth. Cancer Discovery 8 (6) , pp. 764-779. 10.1158/2159-8290.CD-17-0867

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Abstract

Genetic alterations that potentiate PI3K signalling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/amplification correlates with poor prostate cancer patient survival. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110-dependent invasive prostate carcinoma in-vivo. Furthermore, we report PIK3CA mutation and PTEN loss co-exist in prostate cancer patients, and can cooperate in-vivo to accelerate disease progression via AKT-mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de-novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	American Association for Cancer Research
ISSN:	2159-8274
Date of First Compliant Deposit:	19 March 2018
Date of Acceptance:	16 March 2018
Last Modified:	15 Nov 2024 16:15
URI:	https://orca.cardiff.ac.uk/id/eprint/109997

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