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

Helen B. Pearson, Jason Li, Valerie S. Meniel, Christina M. Fennell, Paul Waring, Karen G. Montgomery, Richard J. Rebello, Arthi A. Macpherson, Sarah Koushyar, Luc Furic, Carleen Cullinane, Richard W. Clarkson, Matthew J. Smalley, Kaylene J. Simpson, Toby J. Phesse, Peter R. Shepherd, Patrick O. Humbert, Owen J. Sansom, Wayne A. Phillips

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17 Citations (Scopus)

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 p110α-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.
Original languageEnglish
Pages (from-to)764-779
Number of pages16
JournalCancer Discovery
Volume8
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Cite this

Pearson, Helen B. ; 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. ; Smalley, Matthew J. ; Simpson, Kaylene J. ; Phesse, Toby J. ; Shepherd, Peter R. ; Humbert, Patrick O. ; Sansom, Owen J. ; Phillips, Wayne A. / Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth. In: Cancer Discovery. 2018 ; Vol. 8, No. 6. pp. 764-779.
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title = "Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth",
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 p110α-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.",
author = "Pearson, {Helen B.} and Jason Li and Meniel, {Valerie S.} and Fennell, {Christina M.} and Paul Waring and Montgomery, {Karen G.} and Rebello, {Richard J.} and Macpherson, {Arthi A.} and Sarah Koushyar and Luc Furic and Carleen Cullinane and Clarkson, {Richard W.} and Smalley, {Matthew J.} and Simpson, {Kaylene J.} and Phesse, {Toby J.} and Shepherd, {Peter R.} and Humbert, {Patrick O.} and Sansom, {Owen J.} and Phillips, {Wayne A.}",
year = "2018",
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doi = "10.1158/2159-8290.CD-17-0867",
language = "English",
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Pearson, HB, Li, J, Meniel, VS, Fennell, CM, Waring, P, Montgomery, KG, Rebello, RJ, Macpherson, AA, Koushyar, S, Furic, L, Cullinane, C, Clarkson, RW, Smalley, MJ, Simpson, KJ, Phesse, TJ, Shepherd, PR, Humbert, PO, Sansom, OJ & Phillips, WA 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, vol. 8, no. 6, pp. 764-779. https://doi.org/10.1158/2159-8290.CD-17-0867

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.; 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.; Smalley, Matthew J.; Simpson, Kaylene J.; Phesse, Toby J.; Shepherd, Peter R.; Humbert, Patrick O.; Sansom, Owen J.; Phillips, Wayne A.

In: Cancer Discovery, Vol. 8, No. 6, 01.06.2018, p. 764-779.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth

AU - Pearson, Helen B.

AU - Li, Jason

AU - Meniel, Valerie S.

AU - Fennell, Christina M.

AU - Waring, Paul

AU - Montgomery, Karen G.

AU - Rebello, Richard J.

AU - Macpherson, Arthi A.

AU - Koushyar, Sarah

AU - Furic, Luc

AU - Cullinane, Carleen

AU - Clarkson, Richard W.

AU - Smalley, Matthew J.

AU - Simpson, Kaylene J.

AU - Phesse, Toby J.

AU - Shepherd, Peter R.

AU - Humbert, Patrick O.

AU - Sansom, Owen J.

AU - Phillips, Wayne A.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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 p110α-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.

AB - 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 p110α-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.

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