DRES-05. PREDICTORS OF SENSITIVITY TO COMBINED TEMOZOLOMIDE AND PARP INHIBITOR IN GLIOMA

Abstract

Agents targeting the PARP enzyme family are under active development for the treatment of gliomas. PARP inhibitors (PARPi) can enhance the effect of temozolomide (TMZ) in IDH wild-type glioblastomas, and in addition recent studies have shown that PARP inhibitors can be selectively lethal in IDH1 mutant cancers. Here, we sought to identify predictors of sensitivity and resistance to PARP inhibition in gliomas. We treated 4 IDH1 mutant and 8 IDH wild-type glioma lines, as well as IDH1 mutant fibrosarcoma line HT1080, with TMZ, the PARPi olaparib, or the combination, and assessed cellular growth and survival. In dose response assessments, 7 out of 13 lines were sensitive to olaparib monotherapy (3 IDH1 mutant and 4 IDH wild-type). Combination with TMZ resulted in 6 of 13 lines responding to dual therapy, with an additive effect seen in 5 PARPi monotherapy sensitive gliomas. Notably, 5 of the 6 lines responsive to the combination harbored CDKN2A deletion, compared to none of the non-responsive lines (p=.0021). Treatment with CDK inhibitor palbociclib partially reversed sensitivity to TMZ+PARPi in HT1080, supporting a mechanistic basis for this association. PARPi sensitivity in glioma lines can be augmented by the addition of TMZ. CDKN2A deletion may serve as a potential biomarker identifying tumors sensitive to this combination therapy.