Yes / 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.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/8800 |
| Date | 15 July 2016 |
| Creators | Ross, R.L., McPherson, H.R., Kettlewell, L., Shnyder, Steven, Hurst, C.D., Alder, O., Knowles, M.A. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| 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. |
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