Exploiting synthetic lethality in epithelial ovarian cancer: multi-dimensional approaches beyond DNA damage repair

Synthetic lethality (SL) is a therapeutic approach that selectively target cancer cells via the disruption of two interdependent molecular targets, which together become essential in the cancer context to ensure cancer cell survival. Among anticancer SL strategies, poly ADP-ribose polymerase (PARP) inhibitors have revolutionized the treatment of homologous recombination repair deficient breast and ovarian cancers by targeting the remaining DNA repair mechanisms. However, resistance emergence is nearly universal providing the rationale to expand beyond classical DNA repair targets. Severe DNA lesions like double-strand breaks or extended single-strand stretches trigger the complex DNA damage response signaling cascade (DDR), which provides many SL targets in addition to direct DNA repair mechanisms. Epithelial ovarian cancer is the deadliest gynecologic malignancy, in part because of late detection and treatment resistance, which provides a rich environment to explore the concept of combining multiple targets to produce SL synergies that kill cancer cells. In this context we discuss the interplay among varied components of the DDR including DNA damage signalers, cell cycle regulation, metabolism, epigenetics, and subsequent cell fate decisions like apoptosis or senescence. Based on this knowledge we further explore innovative SL approaches that may elicit or restore drug sensitivity in resistant tumors. Overall, we provide the rationale for multidimensional strategies linking classic DNA repair mechanisms to various molecular vulnerabilities sometimes apparently unrelated or downstream from DNA damage to improve cancer treatment outcomes via more effective and durable therapeutic responses, offering additional options for the personalized treatment of this highly heterogeneous disease.