CBMT-44. COMPREHENSIVE CHARACTERIZATION OF THE INTRINSIC APOPTOTIC MACHINERY REVEALS THE MOLECULAR BLOCKS RESPONSIBLE FOR RESISTANCE TO CELL DEATH IN GLIOBLASTOMA

Abstract

Conventional therapies (e.g., temozolomide (TMZ), Irradiation (IR)) transiently halt tumor growth of glioblastoma (GBM) but fail to induce cell death through apoptosis. Consequently, the inability to kill GBM tumor cells ultimately leads to disease progression and a poor patient survival. The precise molecular mechanisms by which GBM are refractory to apoptosis remain enigmatic. We preformed BH3 profiling to functionally characterize the intrinsic apoptotic machinery and define the molecular ‘blocks’ that obstruct GBM apoptosis under both basal and treatment states. Using a molecularly diverse panel of freshly purified patient tumors, patient-derived neurospheres and patient-derived orthotopic xenografts, we identified that nearly all GBMs have two anti-apoptotic blocks, BCL-xL and MCL-1, which are essential for GBM survival in an untreated state. TMZ or IR (TMZ/IR) disabled the MCL-1 block in a subset of GBMs, leaving tumors exclusively dependent on BCL-xL for survival. Mechanistic studies revealed that TMZ/IR treatment induced p53-dependent expression of the pro-apoptotic protein, PUMA, which subsequently bound to and neutralized MCL-1. Consequently, pharmacological inhibition of BCL-xL in combination with TMZ/IR initiated intrinsic apoptosis and was synergistically lethal in p53 wild-type GBM. These studies identify the existence of two anti-apoptotic proteins that are critical for GBM survival, which can be therapeutically exploited in a molecularly defined subset of GBMs for tumor eradication.