Abstract P19: Mitohormetic Regulation in Multiple Myeloma: Exploiting Mitochondrial Stress Responses for Therapeutic Gain

Abstract Background: Mitohormesis, characterized by adaptive mito-protective mechanisms in response to mitochondrial stress, primarily induced by reactive oxygen species (ROS), plays a pivotal role in Multiple Myeloma (MM). We postulate that malignant plasma cells exploit this process to maintain ROS within a homeostatic range, thereby enhancing mitochondrial fitness and avoiding apoptosis. This study investigates the activation of mitohormesis in MM and explores the therapeutic potential of targeting excessive mitochondrial stress. Methods: We analyzed the activation of the mitochondrial unfolded protein response (UPRMT) across different stages of MM progression using single-cell RNA sequencing data from Vκ*MYC mice. For in vivo studies, we employed NOD-SCID mice, which were either subcutaneously injected with MM cells or tail injected with KMS11/luciferase cells carrying either doxycycline-inducible TIMM23 shRNA lentivirus or control vectors. Results: Our comprehensive analysis reveals a clear correlation between UPRMT activation and MM progression. We observed an increase in UPRMT gene expression in Vκ*MYC mice and in newly diagnosed MM (NDMM) patients, which correlated with progression from precursor disease. Further, higher UPRMT gene signature scores were associated with shorter progression-free survival and overall survival in NDMM. Perturbation of the Translocase of the Inner Membrane 23 (TIM23) complex, a critical regulator of UPRMT, by genetic knockdown or pharmacologic inhibition of TIM23 with MB-10, led to apoptosis in MM cell lines, including those resistant to proteasome inhibitors (PIs). Further, primary patient MM cells were more suspectible to the pro-apoptotic effects of MB-10 then non-transformed cell lines, CD138- non-MM cells and normal donor hematopoietic progenitor cells suggesting the potential for a therapeutic window. MB-10 also induced XBP1 splicing, suggesting that TIM23 inhibition can activate the IRE1/XBP1 branch of the integrated stress response (ISR), potentially overcoming acquired resistance to PIs. Finally, subcutaneous injection of MM cells expressing an inducible shTIMM23 into NOD/SCID mice, followed by doxycycline treatment, confirmed a significant reduction in tumor volume and enhanced survival. These findings were confirmed in a separate study where mice were injected via the tail vein with KMS11/luciferase cells, carrying a doxycycline-inducible shRNA lentivirus observing a significant reduction in tumor growth in mice with inducible shTIMM23 compared to mice with the control vector. Furthermore, a significant improvement in the survival rate was observed in knockdown group. Conclusions: Our findings demonstrate the association of mitohormesis and UPRMT activation with MM progression and adverse clinical outcomes. Targeting mitochondrial import proteins, such as TIM23, disrupts the UPRMT converting it from an adaptive cytoprotective to a cytotoxic proapoptotic response, offering a novel therapeutic strategy for MM. This approach holds promise, including in cases demonstrating resistance to PIs Citation Format: Serges Tsofack, Danielle Croucher, Benjamin Barwick, Zhihua Li, Ahmed Aman, Benjamin Haibe-Kains, Suzanne Trudel, Lawrence Boise, Aaron Schimmer. Mitohormetic Regulation in Multiple Myeloma: Exploiting Mitochondrial Stress Responses for Therapeutic Gain abstract. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5 (2Suppl): Abstract nr P19.