Taselisib enhances effects of anti-microtubule chemotherapic agents in phosphatidylinositol 3-kinase (PI3Kα) mutant breast cancer cell lines

Background

30-50% of breast cancer are characterized by activating mutations of PI3Kα, and higher activity of this pathway is often associated with resistance to conventional therapies. Thus, selective PI3K inhibitors could represent a novel option to prevent treatment resistance, including chemotherapy. Several trials are evaluating the efficacy of Taselisib, a novel selective inhibitor of mutant PI3Kα, in combination with hormonal therapy (NCT02340221, NCT02273973, NCT01296555) or taxanes (NCT01862081) in breast cancer. In preclinical studies, taselisib is active in mutant PI3Kα xenograft models of uterine serous carcinoma and radiosensitizes PI3Kα mutant head and neck squamous carcinomas.

Methods

We evaluated the effect of single agent and combination treatment with different anti-microtubule chemotherapic agents (vinorelbine, taxanes, and eribulin) or taselisib on cell proliferation by MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) assay and on cell survival by apoptosis flow-cytometry analysis. We used five breast cancer cell models: MDA-MB231 (PI3Kα mutation -) and four PI3Kα mutation + with different biological profile (BT474, HER2+ and HR + ; KPL-4, HER2+ HR-; SUM159, TN; MCF7, HR+ HER2-).

Results

A significant activity of vinorelbin or eribulin plus taselisib was observed in PI3Kα mutant cell lines, in both HER2 and HR +/-, in terms of anti-proliferative effects. In addition, taselisib increased the pro-apoptotic effect of eribulin, more than vinorelbin.Combination with taxanes (paclitaxel) resulted less effective. Furthermore, the effects of combination of vinorelbin/eribulin plus taselisib were accompanied by inhibition of PI3K related intracellular proteins (phospho-AKT, AKT, phospho-S6, S6) and phospho-MAPK signaling.

Conclusions

Further investigations are needed to evaluate the combination of anti-microtubule agents and taselisib in breast cancer harbouring alterations of PI3Kα.

Clinical trial identification

Legal entity responsible for the study

Department of Clinical and Experimental Medicine ‘F. Magrassi’, Second University of Naples

Funding

Department of Clinical and Experimental Medicine ‘F. Magrassi’, Second University of Naples

Disclosure

All authors have declared no conflicts of interest.