Synthetic lethality: Molecular co-targeting to restore the DNA repair mechanisms in prostate cancer cells

Resistance to anticancer radiation treatment has a strong negative impact upon morbidity and mortality related to prostate cancer (Liu et al., Radiother Oncol 88(2):258-268, 2008). This justifies the great interest in the advancing efforts toward the design of new molecularly-targeted agents which could improve the therapeutic ratio for aggressive prostate cancers via tumor radio-sensitization (Fan et al., Cancer Res 64(23):8526-8533, 2004). Tumor progression of prostate cancer is associated, as in most of human malignancies, with the sequential loss of function of genes that normally protect against DNA damage. Malignant prostate cells respond to both endogenous and exogenous DNA damage through complex signaling responses. Due to a specific genetic background, or in an acquired manner during tumor progression, PC cell clones show defect in either DNA single-strand break (SSB) and/or double-strand break (DSB) repair, and/or base damage repair (Stewart et al., Biochem Pharmacol 81(2):203-210, 2011), DSBs are the principal responsible for cell killing due to ionizing radiation (Ward 1988). A defective DNA double-strand break repair increases genetic instability of PC cells, could be considered as part of their mutator phenotype (Tyson et al., Prostate 67:1601-1613, 2007). During the last decades, it has emerged the concept of synthetic lethality (Chalmers et al., Semin Radiat Oncol 20(4):274-281, 2010). This concept derives from the observation that the use of a single inhibitor of a DNA repair enzyme leads to the selective killing of tumor cells, bearing a second DNA repair defect (Bryant et al., Nature 434(7035):913-917, 2005; Jones and Plummer, Br J Radiol 81(Spec No 1):S2-S5, 2008; Fong et al., N Engl J Med 361:123-134, 2009). To this end, PARP inhibitors are the well-known class of drugs that have recently been proposed to reach synthetic lethality in DNA repair-defective, radio-resistant prostate tumors. This chapter aims to provide a framework for understanding the recent therapeutic trends designed to overcome radioresistance in prostate cancer via synthetic lethality, we review what it is actually known about the structures and functions of the members of the PARP family of enzymes, outlining a series of open questions that should be addressed in the short time to better guide the development (and the safe clinical use) of PARP inhibitors as new anticancer agents for prostate cancer (Cybulski et al., Cancer Res 64:1215-1219, 2004; Stewart et al., Biochem Pharmacol 81(2):203-210, 2011)