Identification of poziotinib alone or in combination with TDM1 as a pan-HER2 inhibitor

Clinical studies of HER2 targeting agents have shown mutational variant & cancer-specific differences in patient outcomes. Furthermore, the drug sensitivity profiles of HER2 mutational variants have not been fully characterized. To this end, we expressed the 16 most frequently detected HER2 mutations across exons 19-21 into Ba/F3 cells & determined activating potential & drug sensitivity to 13 HER1/2 targeting agents including afatinib, neratinib, dacomitinib, tarloxotinib-TKI, poziotinib, pyrotinib, TDM-1, & trastuzumab. Third generation EGFR TKIs, osimertinib, ibrutinib, & nazartinib were not effective at inhibiting cell viability in cells expressing exon 20 mutations; however, 3rd generation TKIs demonstrated activity against cells expressing D769 exon 19 variants & exon 21 variants. By comparison, covalent, quinazoline-based TKIs, afatinib, neratinib, dacomitinib, tarloxotinib-TKI, & poziotinib, differentially inhibited HER2 mutants across all three exons. Across all HER2 mutation variants & TKIs tested, poziotinib had the lowest average IC50 (1.73nM) & was significantly more effective in reducing cell viability than neratinib & tarloxotinib-TKI (p Citation Format: Jacqulyne P. Robichaux, Monique B. Nilsson, Fahao Zhang, Limei Hu, Junqin He, Marlese Pisegna, Alissa Poteete, John V. Heymach. Identification of poziotinib alone or in combination with TDM1 as a pan-HER2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 347.