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PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma

Ross, R.L.
; 
McPherson, H.R.
; 
Kettlewell, L.
; ; 
Hurst, C.D.
; 
Alder, O.
; 
Knowles, M.A.
Publication Date
2016-07-28
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Keywords
PIK3CA, PI3K signaling, Bladder cancer, Urothelium
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© 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.
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Yes
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openAccess
Accepted for publication
2016-07-15
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Life Sciences Publications
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Ross et al BMC Cancer 2016.pdf
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Abstract
Background: 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.
URI
http://hdl.handle.net/10454/8800
Version
Published version
Citation
Ross RL, McPherson HR, Ketlewell L et al (2016) PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. BMC Cancer. 16: 553.
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https://doi.org/10.1186/s12885-016-2570-0
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Article
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