PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Ross, R.; McPherson, H.; Kettlewell, L.; Shnyder, S.; Hurst, C.; Alder, O.; Knowles, M.
• Is Part Of: BMC cancer. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12
• Subjects: PIK3CA -- PI3K signaling -- Bladder cancer -- Urothelium; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-016-2570-0
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background Many urothelial carcinomas (UC) contain activatingPIK3CA 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 andin vivo tumor growth of cells withPIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspotPIK3CA mutation status. Cells with rarePIK3CA mutations and co-occurringTSC1 orPTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations inTSC1 orPTEN or co-occurringAKT1 and RAS gene mutations were associated with GDC-0941 resistance. Conclusions MutantPIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer.