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.
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.
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.
Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer.
BMC cancer. 2016 Jul 28*** epublish ***
R L Ross, H R McPherson, L Kettlewell, S D Shnyder, C D Hurst, O Alder, M A Knowles
Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK., Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK., Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK., Institute of Cancer Therapeutics, University of Bradford, Richmond Road, Bradford, BD7 1DP, UK., Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK., Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK., Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. .