Pim Kinase Inhibition Promotes Mitochondrial Fission To Combat Chemoresistance In Non-Small Cell Lung Cancer

Abstract Background: Resistance to chemotherapy represents a major obstacle to the successful treatment of non-small cell lung cancer (NSCLC). A fused mitochondrial network is associated with therapeutic resistance, but the factors controlling mitochondrial dynamics in lung cancer are not fully understood. The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Methods: Live cell imaging and microscopy were used to determine the effect of PIM on mitochondrial phenotype and ROS. Biochemical studies were performed to characterize the signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. Xenograft models of lung cancer were used to evaluate the combination of PIM inhibition and chemotherapy. Immunohistochemistry and transmission electron microscopy were used to analyze mitochondrial phenotype, proliferation, and apoptosis in vivo. Results: Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intercellular ROS. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC cells to chemotherapy and produced a synergistic anti-tumor response, characterized by significantly increased ROS and apoptosis. Conclusion: PIM kinase expression is an important mechanism of intrinsic and acquired resistance to chemotherapy in NSCLC. PIM inhibition activates Drp1 to promote mitochondrial fission and superoxide production, sensitizing cancer cells to chemotherapy. These data improve our knowledge of how mitochondria are regulated in cancer and provide justification for combining PIM inhibition with chemotherapy in NSCLC. Citation Format: Shailender S. Chauhan, Rachel K. Toth, Corbin C. Jensen, David F. Kashatus, Andrea L. Casillas, Noel A. Warfel. Pim kinase inhibition promotes mitochondrial fission to combat chemoresistance in non-small cell lung cancer [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 6332.