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PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma
R L Ross1, H R McPherson1, L Kettlewell1
1Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
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.
Insights
Activating PIK3CA mutations drive urothelial carcinoma (UC) growth. Inhibiting PIK3CA shows therapeutic potential in advanced bladder cancer, though resistance can occur with specific co-mutations.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Activating PIK3CA mutations are common in urothelial carcinoma (UC).
- Mutant PIK3CA activates the PI3K pathway, promoting cell proliferation and migration in normal urothelial cells.
- The dependency of advanced UC on PIK3CA and the efficacy of PI3K inhibition remain unclear.
Purpose of the Study:
- To investigate the role of mutant PIK3CA as an oncogenic driver in UC.
- To evaluate the therapeutic potential of PI3K pathway inhibition in advanced UC.
Main Methods:
- Used retrovirus-mediated shRNA to knock down mutant PIK3CA in UC cell lines.
- Assessed effects on pathway activation, proliferation, migration, and tumorigenicity.
- Evaluated the efficacy of the PI3K inhibitor GDC-0941 in UC cell lines with diverse PI3K pathway alterations.
Main Results:
- Knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth, and tumor growth in PIK3CA-mutated UC cells.
- Sensitivity to GDC-0941 was linked to PIK3CA mutation status, with reduced sensitivity in cells harboring rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations.
- Downstream PI3K pathway alterations (TSC1, PTEN, AKT1, RAS) correlated with resistance to GDC-0941.
Conclusions:
- Mutant PIK3CA acts as a significant oncogenic driver in UC cell lines.
- Targeting mutant PIK3CA may offer a viable therapeutic strategy for advanced bladder cancer.
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