Abstract 3691: Dynamic BH3 profiling identifies novel combinations in malignant pleural mesothelioma with in vivo efficacy

Abstract

Abstract Currently, malignant pleural mesothelioma (MPM) is mainly treated with conventional therapies such as surgery, chemotherapy and radiation, and patients often suffer from the lack of second line therapy options. In this study, we aimed to identify efficacious drug combinations in primary MPM patient samples and novel MPM patient-derived xenograft (PDX) models to provide better therapeutic options for MPM patients. BH3 profiling is a functional assay that measures mitochondrial priming of the cell. It uses BH3 peptides derived from the BH3 domain of pro-apoptotic BH3-only Bcl-2 family members to provoke a response from viable mitochondria. When tumor cells are treated with drugs prior to BH3 profiling, early changes in their apoptosis signaling can be captured before frank apoptosis occurs. This method is termed dynamic BH3 profiling (DBP), which has been applied in multiple cancer types to identify efficacious drugs. Here, we used high throughput dynamic BH3 profiling (HTDBP) to assess hundreds of drug treatments simultaneously to identify drug combinations that increased apoptotic priming in primary MPM cells ex vivo. Next, we created novel MPM PDX models and tested these drug combinations to determine the ones that primed MPM PDX cells. The HTDBP result from MPM PDX cells recapitulated the chemical vulnerabilities of the primary MPM cells. Moreover, one of the top combination candidates that comprised of navitoclax (BCL-xL, BCL-2 and BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) was shown to be safe and efficacious in vivo in our CPDM_011x MPM PDX model. Finally, on the molecular level, we revealed that treatment with navitoclax drove the anti-apoptotic dependence of MPM cell lines towards MCL-1, whose level was downregulated by AZD8055 treatment. In this study, we identified a novel drug combination for MPM with HTDBP that consists of navitoclax and AZD8055. In addition, our results further corroborated that DBP, as a functional assay, can be used to rationally construct novel drug combinations to improve treatment outcomes for cancer patients. Citation Format: Danielle S. Potter, Ruochen Du, Kin-Hoe Chow, Keith L. Ligon, Raphael Bueno, Anthony Letai. Dynamic BH3 profiling identifies novel combinations in malignant pleural mesothelioma with in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3691.