Blocking PI3K p110β attenuates development of PTEN-deficient castration-resistant prostate cancer

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buir.contributor.authorÇizmecioğlu, Onur
buir.contributor.orcidÇizmecioğlu, Onur|0000-0002-7608-6950
dc.citation.epage685en_US
dc.citation.issueNumber5en_US
dc.citation.spage673en_US
dc.citation.volumeNumber20en_US
dc.contributor.authorGao, X.
dc.contributor.authorWang, Y.
dc.contributor.authorRibeiro, C. F.
dc.contributor.authorManokaran, C.
dc.contributor.authorChang, H.
dc.contributor.authorVon, T.
dc.contributor.authorRodrigues, S.
dc.contributor.authorÇizmecioğlu, Onur
dc.contributor.authorJia, S.
dc.contributor.authorKorpal, M.
dc.contributor.authorKorn, J. M.
dc.contributor.authorWang, Z.
dc.contributor.authorSchmit, F.
dc.contributor.authorJiang, L.
dc.contributor.authorPagliarini, R.
dc.contributor.authorYang, Y.
dc.contributor.authorSethi, I.
dc.contributor.authorSignoretti, S.
dc.contributor.authorYuan, G.
dc.contributor.authorLoda, M.
dc.contributor.authorZhao, J. J.
dc.contributor.authorRoberts, T. M.
dc.date.accessioned2023-02-24T18:08:03Z
dc.date.available2023-02-24T18:08:03Z
dc.date.issued2022-01-26
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractA 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.en_US
dc.description.provenanceSubmitted by Ezgi Uğurlu (ezgi.ugurlu@bilkent.edu.tr) on 2023-02-24T18:08:03Z No. of bitstreams: 1 Blocking_PI3K_p110β_attenuates_development_of_PTEN-deficient_castration-resistant_prostate_cancer.pdf: 1606268 bytes, checksum: 1ff942bde49ff9044efdaf7a85068471 (MD5)en
dc.description.provenanceMade available in DSpace on 2023-02-24T18:08:03Z (GMT). No. of bitstreams: 1 Blocking_PI3K_p110β_attenuates_development_of_PTEN-deficient_castration-resistant_prostate_cancer.pdf: 1606268 bytes, checksum: 1ff942bde49ff9044efdaf7a85068471 (MD5) Previous issue date: 2022-01-26en
dc.identifier.doi10.1158/1541-7786.MCR-21-0322en_US
dc.identifier.eissn1557-3125
dc.identifier.issn1541-7786
dc.identifier.urihttp://hdl.handle.net/11693/111708
dc.language.isoEnglishen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.relation.isversionofhttps://dx.doi.org/10.1158/1541-7786.MCR-21-0322en_US
dc.source.titleMolecular Cancer Researchen_US
dc.titleBlocking PI3K p110β attenuates development of PTEN-deficient castration-resistant prostate canceren_US
dc.typeArticleen_US

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