Published online Aug 28, 2016. doi: 10.3748/wjg.v22.i32.7275
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
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.
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.