Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

doi:10.3748/wjg.v22.i32.7275

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World Journal of Gastroenterology

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World J Gastroenterol. Aug 28, 2016; 22(32): 7275-7288
Published online Aug 28, 2016. doi: 10.3748/wjg.v22.i32.7275

Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

Shih-Hung Yang, Ting-Chun Kuo, Hsu Wu, Jhe-Cyuan Guo, Chiun Hsu, Chih-Hung Hsu, Yu-Wen Tien, Kun-Huei Yeh, Ann-Lii Cheng, Sung-Hsin Kuo

Shih-Hung Yang, Jhe-Cyuan Guo, Chiun Hsu, Chih-Hung Hsu, Kun-Huei Yeh, Ann-Lii Cheng, Sung-Hsin Kuo, Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei 100, Taiwan

Shih-Hung Yang, Ann-Lii Cheng, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei 100, Taiwan

Shih-Hung Yang, Jhe-Cyuan Guo, Graduate Institute of Clinical Medicine National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei 100, Taiwan

Ting-Chun Kuo, Department of Traumatology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei 100, Taiwan

Hsu Wu, Department of Oncology, National Taiwan University Hospital, Yun-Lin Branch, Yunlin 655, Taiwan

Chiun Hsu, Chih-Hung Hsu, Kun-Huei Yeh, Ann-Lii Cheng, Sung-Hsin Kuo, Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan

Yu-Wen Tien, Department of Surgery, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei 100, Taiwan

Author contributions: Yang SH contributed to drafting the article; Kuo TC, Wu H and Guo JC contributed to acquisition and interpretation of the literature information; Hsu C, Hsu CH, Tien YW, Cheng AL, Yeh KH and Kuo SH contributed to critical revision for important intellectual content and final approval of the version to be published.

Conflict-of-interest statement: The authors declare no conflict of interest.

Correspondence to: Sung-Hsin Kuo, MD, PhD, Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. shkuo101@ntu.edu.tw

Telephone: +886-2-23123456- 67144 Fax: +886-2-23711174

Received: March 29, 2016
Peer-review started: April 5, 2016
First decision: May 12, 2016
Revised: June 20, 2016
Accepted: July 21, 2016
Article in press: July 21, 2016
Published online: August 28, 2016
Processing time: 147 Days and 17.3 Hours

Abstract

Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to co-administration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA double-strand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.

Keywords: Radiotherapy; Pancreatic cancer; DNA damage; DNA repair; Molecular targets

Core tip: Radiotherapy causes DNA damage, including double-strand breaks, which is more readily repaired in normal cells than in cancerous cells. Radiosensitization, using DNA repair pathway inhibitors, has been well documented in various cancer types, including pancreatic cancer. Further development of optimal protocols, for the combined use of these inhibitors with radiotherapy, with/without chemotherapy, is warranted for the clinical treatment of pancreatic cancer.