Abstract 1773: Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers

Abstract

Abstract Background: Neratinib, an oral, irreversible pan-HER tyrosine kinase inhibitor, has exhibited clinical activity against HER2-mutant and HER2 over-expressing cancers. Our previous pre-clinical studies have shown that combining the multi-kinase inhibitor dasatinib with neratinib is highly synergistic in HER2-positive breast cancer. Therefore, the aim of this study was to examine the potential of combining neratinib and dasatinib in HER2 over-expressing/mutant esophagogastric (EG) and ovarian cancer. Methods: The prevalence of HER2 mutation and amplification levels in ovarian and EG cancers was determined using the AACR Project GENIE database. The anti-proliferative effects of neratinib and dasatinib were assessed by acid phosphatase assay in a panel of HER2-altered ovarian (Caov3, OVCAR8, IGROV-1) and EG (NCI-N87, OE19) cancers. Synergy was assessed using Combenefit software with the Loewe additivity model, with additivity and synergy > 0 and antagonism < 0. Western blotting was used to examine the basal expression of HER2 and downstream signalling activity and to investigate the signalling effects of drug treatment in HER2-mutant OVCAR8 cells. Results: HER2 was the most commonly amplified gene in EG cancers (14.1%) and was also amplified in 2.4% of ovarian cancers. HER2 mutations occurred in 6.1% of EG and 1.5% ovarian cancers. All five cell lines tested displayed nanomolar sensitivity to single agent neratinib or dasatinib (Table). The combination of neratinib and dasatinib was synergistic in all cell lines. The greatest synergy was observed with low concentrations of neratinib in EG cell lines. Synergistic interactions occurred across a range of concentrations with both drugs in ovarian cancer cell lines. Antagonism was not observed at any concentration tested. Neratinib plus dasatinib inhibited Src and MAPK activity in OVCAR8 cells. Neratinib and dasatinib in ovarian and EG cancersCell linesCancertypeNeratinib EC50 value (nM)Dasatinib EC50 value (nM)Combination effectNCI-N87Esophagogastric0.188979SynergismOE19Esophagogastric0.432284SynergismOVCAR8Ovarian16281SynergismIGROV-1Ovarian1706SynergismCaov3Ovarian13730Synergism Conclusions: These data suggest that the addition of dasatinib may enhance the anti-cancer effect of neratinib in HER2-driven ovarian and EG cancers and warrants further investigation. Citation Format: Neil T. Conlon, Keshia Kroh, John Crown, Denis M. Collins. Targeting HER2 and Src in HER2-driven ovarian and esophagogastric cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1773.