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

Abstract

Objective To evaluate the efficacy of Taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification. Methods Sensitivity 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. Results Four 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). Conclusions Taselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.

Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo

“…The effect of single agent neratinib and taselisib on the viability of 3 primary USC cell lines (i.e., USPC-ARK-2, 20, 21) has been previously reported (23, 27). The effect of neratinib on the viability and IC 50 of USPC-ARK-1 cell line was determined in flow-cytometry based assays as previously described (23, 27).…”

Emerging strategies for targeting PI3K in gynecologic cancer

“…These findings have prompted numerous pre-clinical studies that have demonstrated that PI3K inhibition can impair the proliferation of endometrial cancer cells and that loss of PTEN or PIK3CA mutation may serve as a biomarker associated with response to novel agents that antagonize PI3K [45][46][47][48]. In a large study evaluating pan PI3K inhibition, cell lines across many disease sites with a PIK3CA mutation and PTEN loss manifested the greatest sensitivity [48].…”

“…It has been shown that 70% of HER2 gene amplified endometrial cancers harbor a concurrent gain of function mutation in PIK3CA [50]. Numerous studies have demonstrated that PIK3CA mutation uncouples in vitro and in vivo response to anti-HER2 therapies and that adding concurrent PI3K inhibition, either directly or via downstream mTOR inhibition, can restore efficacy [47,50,51].…”

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

“…Unlike other PIK3 inhibitors, taselisib is designed to bind the ATP-binding pocket of PI3K with selective preference for the mutated form of PIK3CA [73]. In preclinical models, taselisib caused growth inhibition in both HER2+ and PIK3CA-mutated cell lines and was highly active at reducing tumor growth in xenografts mouse harboring PIK3CA mutation and overexpressing HER2 [74]. The combination of taselisib and letrozole in a BC cell line engineered to express aromatase decreased cellular viability and increased apoptosis relative to either single agent [75].…”