Dual inhibition of PI3K and PARP demonstrates synergistic anti-tumor activity in endometrioid endometrial cancer patient derived xenografts

(USC) cell lines with and without HER2/neu gene amplification to afatinib, an EGFR, HER2, and HER4 irreversible tyrosine kinase inhibitor and to test the efficacy of afatinib in the treatment of HER2 amplified USC xenografts. Methods: Eight of fifteen primary USC cell lines (4 with HER2 amplification and 4 without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signaling and cell-cycle distribution were determined by flow cytometry assays. Mice harboring xenografts of HER2/neu amplified USC were treated with afatinib by gavage to determine the effect on tumor growth and overall survival. Results: Primary chemotherapy–resistant USC cell lines harboring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± SEM IC50 = 0.0056 μM± 0.0006 μM) and significantly more sensitive than HER2/neu non-amplified USC cell lines (mean ± SEM IC50 = 0.563 μM± 0.092 μM, P b 0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2 amplified tumor xenografts improving overall survival (p = 0.0017). Conclusions: Afatinib may be highly effective against HER2/neu amplified chemotherapy resistant USC. The investigation of afatinib in patients harboring HER2/neu amplified USC is warranted.