Abstract 1595: The poly(ADP-ribose) polymerase inhibitor BMN 673 has single agent activity and augments cytotoxicity of radiation in human head and neck tumor cell line in vitro: a novel strategy for radiosensitization in head and neck cancer.
Authors: Shin David D. , Ratikan Josephine , Manivong Kanthinh , Chalukya Meenal , Post Leonard , Shen Yuqiao (Jerry) , McBride William , Schaue Dörthe , Slamon Dennis J. , Finn Richard S. 
Published: August 2014

Background and purpose: Current treatment of head and neck cancer generally involves a combination of surgery, radiation and chemotherapy. Clinical outcomes for many patients remain suboptimal, and novel therapeutic strategies are needed. Targeted inhibition of poly(ADP-Ribose) polymerase (PARP), a key DNA repair enzyme, has been actively investigated in cancer medicine. BMN 673 is a potent orally active inhibitor of PARP, currently in phase I clinical trials in solid and hematologic malignancies. We hypothesized BMN 673 might have single agent activity in a subset of head and neck cancers and could significantly augment the effects of radiation in this disease. To test this strategy, we performed preclinical studies to evaluate single agent activity of BMN 673 in a large panel of human head and neck cell lines. We also aimed to define interactions between BMN 673 and radiation in these models.

Materials and methods: Human head and neck cell lines (N=32) were treated with single-agent BMN 673 for 5 days, and in vitro growth inhibition assays were performed. Further, four cell lines were studied in colony formation assays by seeding and treating them with BMN 673 at 1, 10, or 100 nM (or vehicle) for 24 hours, followed by mock or 4 Gy irradiation (300kV, 10mA). Cells were incubated for 14 or 20 days and stained with crystal violet for colony enumeration. Each experiment was performed in triplicates. Survival fraction was calculated: (number of colonies for treated cells/number of cells plated)/(number of colonies for corresponding control/number of cells plated).

Results: A gradation of sensitivity was observed with BMN 673 monotherapy: IC 50 ranges from 0.1 to 10 μM. Radiation alone reduced colony forming ability of the cells by 26% in UMSCC-5 and by approximately 65% in other three cell lines (UMSCC-6, 12, and 38). These cells exhibited enhanced cytotoxicity with addition of BMN 673 to radiation in a dose-dependent manner. Addition of 100nM of BMN 673 resulted in 80% reduction in the number of surviving colonies in the relatively radio-resistant UMSCC-5 and in 88-100% reduction in other cell lines. All changes were statistically significant.

Conclusions: In vitro assays demonstrate human head and neck cancer cells exhibit relative growth sensitivity to BMN 673 monotherapy. In addition, radiation-induced cytotoxicity is augmented by the addition of BMN 673 to radiation in a dose-dependent manner. Notably, one relatively radio-resistant line was rendered radio-sensitive with the addition of BMN 673 to radiation. These data support a role of PARP inhibition as monotherapy and/or in combination with radiotherapy, representing a potential novel translational therapeutic strategy in head and neck cancers that warrant clinical testing.

Citation Format: David D. Shin, Josephine Ratikan, Kanthinh Manivong, Meenal Chalukya, Leonard Post, Yuqiao (Jerry) Shen, William McBride, Dörthe Schaue, Dennis J. Slamon, Richard S. Finn. The poly(ADP-ribose) polymerase inhibitor BMN 673 has single agent activity and augments cytotoxicity of radiation in human head and neck tumor cell line in vitro: a novel strategy for radiosensitization in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1595. doi:10.1158/1538-7445.AM2013-1595