ATR inhibition as a novel radiosensitization strategy for glioblastoma
OC-0425
Abstract
ATR inhibition as a novel radiosensitization strategy for glioblastoma
Authors: Bipasha Mukherjee1, Suman Kanji1, Nozomi Tomimatsu1, John Floyd1, Sandeep Burma1
1UT Health Science Center at San Antonio, Neurosurgery, San Antonio, USA
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Purpose or Objective
Glioblastomas (GBM) are lethal brain tumors for which surgical resection followed by treatment with ionizing radiation (IR) and concurrent administration of Temozolomide (TMZ) is the mainstay of therapy. These tumors are extremely radioresistant, and resistance to radiation is one of the primary causes of therapy failure. Therefore, there is an urgent need for rational radiosensitization approaches to improve GBM therapy. IR induces double strand breaks (DSBs) in the DNA, and these are extremely deleterious lesions that can be repaired either by error-prone non-homologous end joining (NHEJ) or the error-free homologous recombination (HR) pathway. Research in our and other laboratories has shown that the ATR kinase promotes the HR pathway. We therefore hypothesized that ATR inhibition would block DSB repair in rapidly-dividing GBM cells that are HR dependent but not in non-dividing normal brain cells that are dependent upon NHEJ for repair.
Material and Methods
A panel of GBM cell lines and normal human astrocytes were treated with VX-803 and/or IR and assessed for multiple endpoints including HR, DSB repair, and cell survival. PDX mouse models of GBM were treated with VX-803 followed by XRT and monitored for tumor growth and survival of tumor bearing mice. In addition, the effect of the drug on tumor cells versus normal brain cells was assessed by immunostaining for DSB markers.
Results
We find that VX-803 blocks HR and DSB repair in a panel of GBM cell lines but does not significantly affect repair in non-dividing normal human astrocytes. Hence, treatment with VX-803 sensitizes GBM lines to IR in vitro as measured by the colony formation assay. In vivo, we find that the drug can cross the blood-brain barrier and, in conjunction with IR, block DNA repair in intracranial tumors, attenuate tumor growth, and consequently extend survival of tumor-bearing mice. Importantly, the drug does not significantly affect DSB repair in normal brain cells indicating that ATR inhibition might selectively block repair in GBM cells resulting in increased tumor control with minimal normal tissue toxicity.
Conclusion
Our results indicate that regulation of HR by ATR is critical for optimal DSB repair, especially in rapidly-dividing GBM cells, and that ATR inhibition could be used to improve GBM radiotherapy in the clinic.