Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

SIMPLE SUMMARY: Colorectal cancer (CRC) is among the most common cancers and the third leading cause of cancer deaths worldwide. Despite the identification of alterations in DNA repair genes and the resulting genomic instability in sub-populations of CRC, therapies that exploit defects in DNA repair pathways or high level of replicative stress have been explored only in breast, ovarian, and other tumor types, but not yet systematically in CRC. Here, we discuss how targeting genes involved in the responses to replication stress and the repair of DNA double-strand breaks (DSBs) could provide new therapeutic opportunities to treat CRCs and have the potential to confer increased sensitivity to current chemotherapy regimens, thus, expanding the spectrum of therapy options, and potentially improving clinical outcomes for CRC patients. ABSTRACT: Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies.