Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo

•This is the first research article to evaluate the efficacy of Taselisib in USC.•Taselisib may represent a novel therapeutic agent for advanced/recurrent USC.•PIK3CA mutation and HER2/neu amplification determine sensitivity of USC to taselisib.

ObjectiveTo evaluate the efficacy of taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification.MethodsSensitivity to taselisib was evaluated by flow-cytometry viability assays in vitro against nine primary USC cell lines. Cell cycle distribution and downstream signaling were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry. Preclinical efficacy of taselisib was also evaluated in vivo in a mouse model.ResultsFour USC cell lines harbored HER2/neu gene amplification by FISH and two of them harbored oncogenic PIK3CA mutations. Taselisib caused a strong differential growth inhibition in both HER2/neu FISH positive and HER2/neu FISH positive/PIK3CA mutated USC cell lines when compared to lines that were FISH negative and PIK3CA wild type (taselisib IC50 mean ± SEM = 0.042 ± 0.006 μM in FISH + versus 0.38 ± 0.06 μM in FISH-tumors, P < 0.0001). Taselisib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and dose-dependent decline in the phosphorylation of S6. Taselisib was highly active at reducing tumor growth in vivo in USC mouse xenografts harboring PIK3CA mutation and overexpressing HER2/neu (P = 0.007). Mice treated with taselisib had significantly longer survival when compared to control mice (P < 0.0001).ConclusionsTaselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.