Abstract B034: Targeting the HER family/Src pathways in ovarian cancer

Abstract Background: Targeting EGFR and HER2 has been highly successful across several cancer types, but has been underexplored in ovarian cancer (OC), with several studies suggesting EGFR and HER2 is commonly over-expressed in epithelial OC. The irreversible pan-HER inhibitor neratinib has demonstrated clinical activity in HER2-mutant and HER2-overexpressing cancers and we have previously shown that neratinib plus the multi-kinase inhibitor dasatinib is highly synergistic in ovarian and breast cancers. Targeting the Src family kinases has involved the use of broad multi-kinase inhibitors such as dasatinib and bosutinib. However, NXP-900 is a novel orally bioavailable small molecule selective inhibitor of Src family kinases that may have synergistic efficacy with reduced off-target effects. The aim of this study was to investigate the potential of NXP-900 in combination with the pan-HER inhibitor neratinib in OC. Methods: The anti-proliferative effects of Src inhibitors, dasatinib (multi-kinase) or NXP-900 (Src selective), plus neratinib were tested in SKOV3, OVCAR3, PEO1 and IGROV-1 cell lines. Synergism was assessed using Combenefit software with the Loewe additivity model. Induction of caspase 3/7 activation, a marker of apoptosis, and the effects on cell migration with single agent and combination treatment were assessed using the Incucyte S3 imaging system. Downstream signaling alteration were investigated by Western blotting. Results: The combination of neratinib with either dasatinib or NXP-900 was highly synergistic across the cell lines. NXP-900 had little anti-proliferative activity as a single agent but significantly enhanced the effect of neratinib at nanomolar concentrations. Dasatinib showed potent single agent activity and synergies with neratinib across cell lines. SKOV3 cell line displayed the greatest synergy with both combinations and was selected for further characterization. Src inhibition alone inhibited cell migration, and further migration suppression was observed with the addition of neratinib. The combination stimulated apoptosis induction and resulted in on-target signaling inhibition in SKOV3 cells. Conclusions: This pre-clinical study showed that inhibition of the HER family and Src family kinases may have a strong anti-proliferative effect in OC models. Citation Format: Neil T. Conlon, Elena Mörhle, Denis M. Collins, John Crown. Targeting the HER family/Src pathways in ovarian cancer abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B034.