DDDR-67. BMP signaling modulates apoptotic and non-apoptotic cell death in glioblastoma

Abstract Recurrence occurs in approximately 90% of glioblastoma (GBM) patients, in part due to the tumors becoming resistant to cell death in response to existing therapies. These therapies often trigger apoptosis; however, apoptosis is only one of several different forms of cell death. We hypothesize that activating non-canonical death mechanisms could provide a back door to killing treatment-resistant GBM cells. To test this hypothesis, we first developed a new imaging-based high-throughput method to directly quantify cell death in 3D models. Using this method, we find patient-derived GBM spheroids to be resistant to the induction of cell death in response to various standard-of-care and experimental therapeutic compounds. To further investigate mechanisms underlying this resistance, we screened a panel of extracellular protein ligands for the modulation of cell death response. We find that bone morphogenic protein (BMP) signaling increases resistance to several apoptosis-inducing compounds, including temozolomide and tyrosine kinase inhibitors. Intriguingly, BMP signaling simultaneously enhanced sensitivity to non-apoptotic cell death triggered by the small molecule CIL56. Efforts are ongoing to further understand how BMP signaling governs apoptotic and non-apoptotic cell death mechanisms. Nevertheless, our results suggest a novel approach to treating GBM, centered upon the modulation of BMP signaling combined with the use of agents that induce non-apoptotic cell death.