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.
Highlights
Lung cancer remains the leading cause of cancer incidence and mortality worldwide [1]
Previous studies from our laboratory showed that poly (ADP-ribose) polymerase (PARP) inhibitor effectively targeted triple negative breast cancer cells irrespective of their BRCA1 status [23]
Our laboratory demonstrated that PARP inhibitor LT626 synergizes with cisplatin, oxaliplatin, and SN-38 in colorectal cancer cell lines [26]
Summary
Lung cancer remains the leading cause of cancer incidence and mortality worldwide [1]. According to the American Cancer Society in 2016, an estimated 158,080 Americans are expected to die from lung cancer [2]. Nonsmall cell lung cancer (NSCLC) accounts for 80–90% of all lung cancers and the standard of care for early-stage NSCLC is surgery. Surgery is not a feasible option for most NSCLC patients who either cannot tolerate surgical stress or postoperative recovery, or for whom the disease burden is too extensive. Clinical trials in NSCLC patients found that treatment based on a broad use of cytotoxic chemotherapies, with third generation platinum based drugs had reached its therapeutic plateau [3]. Studies have shown that for locally advanced NSCLC, conventional fractionated radiotherapy with concurrent chemotherapy was better than simple radiotherapy or sequential radiochemotherapy [4, 5]
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