Abstract 1622: Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial bioenergetics and synergistically enhances cell death induced by BCL 2 inhibitors in lung cancer and leukemia cells

Background: Bone morphogenic proteins (BMP) proteins are highly overexpressed in non-small cell lung carcinomas (NSCLC) and leukemia cells. Studies have shown that BMP signaling is growth promoting and enhances survival of cancer cells. The mechanism by which BMP signaling promotes tumorigenesis has not been fully elucidated. Our prior studies revealed that BMP signaling suppresses AMP kinase activation in lung cancer cells, which is conserved in C elegans. We also found that the BMP2 ligand significantly suppressed tricarboxylic acid (TCA) cycle intermediates in lung cancer cells. These studies suggest that BMP signaling suppresses mitochondrial bioenergetics. To better understand the role of BMP signaling in cancer, our team developed specific small molecules inhibiting the BMP type 2 receptor (BMPR2). In this study, the BMPR2 inhibitor JL189 and genetically engineered BMPR2 knockout (KO) cells were used to examine the effects of BMP signaling on mitochondrial bioenergetics. We also examined if altering mitochondrial bioenergetics increased cytotoxicity of BCL-2 inhibitors, which promote mitochondrial induced apoptosis. Mitochondrial metabolic metabolites were measured by liquid chromatography mass spectrometry. Mitochondrial mass was determined by MitoTracker Green labeling quantified by flow cytometry. Metabolomic studies demonstrated that JL189 significantly increased TCA intermediates in lung cancer cells. Knockout of BMPR2 in A549 cells also significantly increased TCA cycle intermediates. Agilent Seahorse analyzer demonstrated that BMPR2 inhibition increased oxidative phosphorylation in NSLC cells. Inhibition of BMPR2 signaling with JL189 or KO cells increased mitochondrial mass in NSCLC and leukemia cell lines. JL189 synergistically enhanced cell death induced by the BCL-2 inhibitors ABT-263 (navitoclax) and ABT-199 (venetoclax) in both NSCLC (A549, H1299, Calu-1) and leukemia cell lines (Jurkat, Kasumi-1, THP-1). By Western blot analysis, the activation of caspase-3 was higher in cancer cells treated with JL189 combined with ABT-263 compared to each compound alone. Cell death induced by BMPR2 inhibition alone and in combination with BCL-2 inhibitors was more pronounced in leukemia cells lines compared to NSCLC cell lines. Conclusion: Inhibition of BMPR2 signaling increased mitochondrial biogenesis in NSCLC and leukemia cell lines, suggesting that the cancer cells are more susceptible to mitochondrial induced cell death. BMPR2 inhibition also significantly increased cancer cell death when combined with a BCL-2 inhibitor. Priming the mitochondria with a BMPR2 inhibitor may represent a novel strategy to enhance cancer therapeutics that promote mitochondrial induced apoptosis. Our data suggests that BMPR2 inhibition may be more effective in leukemia compared to NSLC. Citation Format: Ashley Toussaint, Manohar Singh, Arindam Mondal, Dongxuan Jia, John Langenfeld. Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial bioenergetics and synergistically enhances cell death induced by BCL 2 inhibitors in lung cancer and leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1622.