ABSTRACT
Introduction to DNA Damage Response Pathways and Potential Targets for Drug Modulation .............................................................................................. 423
Role of PARP in DNA Damage Response ........................................................424 Role of Chk1 in DNA Damage Response ......................................................... 427
Summary of Preclinical Data Supporting Clinical Development of PARPi .......... 427 Chemo-and Radio-Potentiation ........................................................................ 427 Synthetic Lethality: Single-Agent Use of PARP Inhibitors .............................. 428 Clinical Development of PARP Inhibitors ........................................................ 428 Chemotherapy Combination Trials ................................................................... 429 Further Clinical Studies in Combination with Chemotherapy .......................... 431 Summary of Single-Agent Clinical Trials ......................................................... 432
Summary of Preclinical Data Supporting Clinical Development of Chk1 Inhibitors .................................................................................................. 434
Single-Agent Clinical Trials with Chk1 Inhibitors ........................................... 435 Clinical Trials of Chk1 Inhibitors with Chemotherapy ..................................... 435 Summary and Future Directions ....................................................................... 436
References .............................................................................................................. 437
There are five recognized pathways that protect the genome by signaling specific types of DNA damage and carrying out repair (reviewed in1-3). In cancer cells, it is recognized that mutations in DDR pathways can predispose to cancer and are hallmarks of many of the hereditary cancer syndromes.4-6 Additionally, it is felt that in many situations, once a tumor cell has developed, the DDR pathways can be used by the tumor cell to overcome many standard anticancer treatments and hence are a cause of treatment resistance. There is increasing evidence in the literature that tumor tissue has high levels of some elements of the DNA repair pathways,7-11 potentially enhancing the ability to use these pathways to repair damage caused by anticancer therapies. These two features of cancer cells present opportunities for the development of treatments using inhibitors of the DDR pathways. Blocking a second pathway in a tumor cell deficient in a key oncogenic pathway can cause tumor cell death by synthetic lethality, and the combination of inhibitors with DNA-damaging drugs or radiation is a potential mechanism to increase cytotoxicity.
