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dc.contributor.authorRoss, R.L.
dc.contributor.authorMcPherson, H.R.
dc.contributor.authorKettlewell, L.
dc.contributor.authorShnyder, Steven D.
dc.contributor.authorHurst, C.D.
dc.contributor.authorAlder, O.
dc.contributor.authorKnowles, M.A.
dc.date.accessioned2016-08-15T09:12:13Z
dc.date.available2016-08-15T09:12:13Z
dc.date.issued2016-07-28
dc.identifier.citationRoss RL, McPherson HR, Ketlewell L, Shnyder SD, Hurst CD, Alder O and Knowles MA (2016) PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. BMC Cancer. 16: 553.en_US
dc.identifier.urihttp://hdl.handle.net/10454/8800
dc.descriptionYesen_US
dc.description.abstractBackground: Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. Methods: We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. Results: Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. Conclusions: Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttp://dx.doi.org/10.1186/s12885-016-2570-0en_US
dc.rights© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
dc.subjectPIK3CA; PI3K signaling; Bladder cancer, Urotheliumen_US
dc.titlePIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinomaen_US
dc.status.refereedYesen_US
dc.date.Accepted2016-07-15
dc.typeArticleen_US
dc.type.versionpublished version paperen_US
refterms.dateFOA2018-07-25T15:24:34Z


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