Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer.
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.
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
SH
Yang
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.
Ting-Chun
TC
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.
Hsu
H
Wu
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.
Jhe-Cyuan
JC
Guo
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.
Chiun
C
Hsu
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.
Chih-Hung
CH
Hsu
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.
Yu-Wen
YW
Tien
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.
Kun-Huei
KH
Yeh
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.
Ann-Lii
AL
Cheng
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.
Sung-Hsin
SH
Kuo
D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors; D003131:Combined Modality Therapy; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors; D006801:Humans; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D051747:DNA-Activated Protein Kinase
DNA damage; DNA repair; Molecular targets; Pancreatic cancer; Radiotherapy