Oncotarget

Research Papers:

Poly (ADP-ribose) polymerase inhibitor, an effective radiosensitizer in lung and pancreatic cancers

Kedar Hastak, Steven Bhutra, Renate Parry and James M. Ford _

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Oncotarget. 2017; 8:26344-26355. https://doi.org/10.18632/oncotarget.15464

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Abstract

Kedar Hastak1, Steven Bhutra2,3, Renate Parry4, James M. Ford1

1Department of Medicine, Division of Oncology, Stanford University, Stanford CA 94305, USA

2Department of Biology, Stanford University, Stanford CA 94305, USA

3Current address: Department of Medicine, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA

4Varian Medical Systems, Palo Alto, CA 94306, USA

Correspondence to:

James M. Ford, email: jmf@stanford.edu

Keywords: PARP inhibitor, fractionated radiation, combination therapy, radiosensitizer, lung cancer

Received: November 02, 2016     Accepted: February 06, 2017     Published: February 17, 2017

ABSTRACT

The development of stereotactic body radiation therapy (SBRT) has revolutionized radiation therapy for lung cancers and is an emerging treatment option for pancreatic cancers. However, there are many questions on how to optimize its use in chemoradiotherapy. The most relevant addition to radiotherapy regimens are inhibitors of DNA repair and DNA damage response pathways. One such class of agents are inhibitors of poly (ADP-ribose) polymerase (PARP). In this study we examined the effects of the PARP inhibitor LT626 in combination with ionizing radiation in lung and pancreatic cancers. Our study demonstrated that combination treatment with LT626 and radiation effectively inhibited growth in lung and pancreatic cancer cell lines, better than individual treatment alone. Combination treatment also increased expression of γH2AX and 53BP1 foci and upregulated expression of phosphorylated ATM, ATR and their respective kinases. Using in vivo lung cancer xenograft models we demonstrated that LT626 functioned as an effective radiosensitizer during fractionated radiation treatment, leading to significant decrease in tumor burden and doubling the median survival compared to control group. Overall our in vitro and in vivo studies showed that PARP inhibitor LT626 acted synergistically with radiation in lung and pancreatic cancers.


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