Mechanism of Radiosensitization by the Chk1/2 Inhibitor AZD7762 Involves Abrogation of the G2 Checkpoint and Inhibition of Homologous Recombinational DNA Repair

Cancer Research - Tập 70 Số 12 - Trang 4972-4981 - 2010
Meredith A. Morgan1,2,3, Leslie A. Parsels1,2,3, Lili Zhao1,2,3, Joshua D. Parsels1,2,3, Mary A. Davis1,2,3, Maria Hassan1,2,3, Sankari Arumugarajah1,2,3, Linda Hylander-Gans1,2,3, Deborah Morosini1,2,3, Diane M. Simeone1,2,3, Christine E. Canman1,2,3, Daniel P. Normolle1,2,3, Sonya Zabludoff1,2,3, Jonathan Maybaum1,2,3, Theodore S. Lawrence1,2,3
1AstraZeneca R&D Boston, Waltham, Massachusetts
2Authors' Affiliations: Departments of 1Radiation Oncology, 2Pharmacology, and 3Surgery, University of Michigan Medical School; 4Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; and 5AstraZeneca R&D Boston, Waltham, Massachusetts
3Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Tóm tắt

Abstract The median survival for patients with locally advanced pancreatic cancer treated with gemcitabine and radiation is approximately 1 year. To develop improved treatment, we have combined a Chk1/2-targeted agent, AZD7762, currently in phase I clinical trials, with gemcitabine and ionizing radiation in preclinical pancreatic tumor models. We found that in vitro AZD7762 alone or in combination with gemcitabine significantly sensitized MiaPaCa-2 cells to radiation. AZD7762 inhibited Chk1 autophosphorylation (S296 Chk1), stabilized Cdc25A, and increased ATR/ATM–mediated Chk1 phosphorylation (S345 Chk1). Radiosensitization by AZD7762 was associated with abrogation of the G2 checkpoint as well as with inhibition of Rad51 focus formation, inhibition of homologous recombination repair, and persistent γ-H2AX expression. AZD7762 was also a radiation sensitizer in multiple tumor xenograft models. In both MiaPaCa-2- and patient-derived xenografts, AZD7762 significantly prolonged the median time required for tumor volume doubling in response to gemcitabine and radiation. Together, our findings suggest that G2 checkpoint abrogation and homologous recombination repair inhibition both contribute to sensitization by Chk1 inhibition. Furthermore, they support the clinical use of AZD7762 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. Cancer Res; 70(12); 4972–81. ©2010 AACR.

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