Abstract PR19: Targeting DNA double-strand break repair to potentiate radio- and chemo-therapy of glioblastoma

Glioblastomas (GBMs) are lethal brain tumors which are treated with ionizing radiation (IR) in combination with the DNA alkylating agent temozolomide (TMZ). Unfortunately, not all GBMs respond to therapy, and most of them quickly acquire resistance to TMZ and recur. In order to better understand the molecular basis for therapy-driven TMZ resistance, mice bearing orthotopic GBM xenografts were subjected to protracted TMZ treatment, and cell lines were generated from the primary (untreated) and recurrent (TMZ-treated) tumors. We found that cell lines derived from recurrent tumors were more resistant to TMZ in vitro compared to cell lines derived from primary tumors. We also found that the increased resistance to TMZ was due to augmented repair of TMZ-induced DNA double strand breaks (DSBs). TMZ induces DNA replication-associated DSBs that are primarily repaired by the homologous recombination (HR) pathway. Augmented HR appears to underpin TMZ resistance in the recurrent lines as these cells were cross-resistant to other agents that induce replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCEs). We have recently shown that CDKs 1 and 2 promote HR in S and G2 phases of the cell cycle, in part, by phosphorylating the exonuclease EXO1. We hypothesized, therefore, that blocking CDKs 1 and 2 might be a viable strategy for re-sensitizing recurrent tumors to TMZ. Indeed, we found that CDK in...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapies Targeting Checkpoints and Mismatch Repair: Oral Presentations - Proffered Abstracts Source Type: research