Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, and is universally fatal. The DNA alkylating agent temzolomide (TMZ) is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. 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. As expected, the cells derived from primary tumors were sensitive to TMZ while the cells from the recurrent tumors were significantly resistant to the drug. Importantly, the acquired resistance to TMZ in the recurrent lines was not driven by re-expression of MGMT or loss of MMR, but was due to accelerated 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 induced replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCEs). Furthermore, in light of recent studies demonstrating that CDK1 and CDK2 promote HR, it was found that CDK1/2 inhibitors countered the heightened HR in recurrent tumors and sensitized these therapy-resistant tumor cells to TMZ. Implications: Augmented homologous recombination repair is a novel mechanism underlying acquired-TMZ resistance in GBM, and this raises the possibility of improving the therapeutic response to TMZ by targeting HR with small molecule inhibitors of CDKs 1 and 2.
- Received April 13, 2016.
- Revision received June 14, 2016.
- Accepted June 16, 2016.
- Copyright ©2016, American Association for Cancer Research.