PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma

• Published in: BMC cancer 2016-07, Vol.16 (1), p.553-553, Article 553
• Main Authors: Ross, R L, McPherson, H R, Kettlewell, L, Shnyder, S D, Hurst, C D, Alder, O, Knowles, M A
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antibodies; Biomarkers; Bladder cancer; Blotting, Western; Cancer therapies; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Cell Line, Tumor; Cell Movement - physiology; Cell Proliferation - physiology; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Clinical trials; Gene Knockdown Techniques; Health aspects; Heterografts; Humans; Immunohistochemistry; Kinases; Male; Medical prognosis; Metastasis; Mice; Mice, Inbred BALB C; Mutation; Phosphoinositides; Tumors; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-016-2570-0

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.