Introduction: Glioblastoma, the most common primary brain tumor, is often initially responsive to alkylating chemotherapeutic-containing regimens, but invariably these tumors return with few effective therapeutic options. Emergence of mismatch repair (MMR) pathway deficiency via MSH6 inactivation in post-alkylator glioblastomas has been established as a significant mechanism of treatment resistance.
Methods: Here, we examine the susceptibility of MSH6-mutated glioblastoma lines and MSH6-inactivated glioma stem cell lines to treatment with the alkylating chemotherapeutic agent temozolomide (TMZ) paired with the poly (ADP-ribose) polymerase 1 (PARP) inhibitor veliparib (VPB, also known as ABT-888), a combination that is currently in phase II clinical trials.
Results: We show that addition of VPB restores TMZ sensitivity in these previously TMZ-resistant lines in an MSH6-specific manner (termed “synthetic enhancement”). We further show that combination therapy can prevent the emergent outgrowth of MSH6 mutant stem cells, and thus can close off this treatment escape pathway at its potential source. Recovery of tumor cell sensitivity is associated with re-accumulation of phosphorylated Chk1 and phosphorylated H2AX eventually leading to DNA breaks, indicating restoration of a common mechanistic pathway of treatment effect.
Conclusions: These results identify a genetically-defined subgroup of recurrent glioblastomas which may benefit from targeted combination therapy with TMZ and VPB.
Patient Care: The identification of a genetically defined subgroup which is responsive to combination therapy is critical in creating chemotherapy regimens, showing clinical efficacy, and improving patient outcomes.
Learning Objectives: By the conclusion of this session, participants should be able to understand the genetics surrounding a major pathway of alkylator resistance in glioblastoma stem cells and the mechanism of its reversal using combination temozolomide and veliparib therapy in a genetically defined subgroup.