Translesion Synthesis Inhibitors as Anti-Cancer Adjuvant Agents

The translesion synthesis (TLS) pathway is a major mechanism through which cancer cells replicate past DNA lesions and promote chemoresistance. TLS allows cancers to survive genotoxic chemotherapy and increases the rate of mutation in tumors leading to drug-resistant cells. Cancer cells use a set of specialized low-fidelity TLS DNA polymerases to copy over lesions with Rev1 serving as a key scaffolding protein. Suppressing Rev1 activity sensitizes cancers to genotoxic chemotherapy and reduces the onset of chemoresistance by decreasing tumor mutation rate. Disruption of the Rev1/polζ-dependent TLS selective inhibitors has demonstrated the ability to sensitize cancer cells to platinating agents and reduce mutagenesis in tumors. This study identifies small molecule Rev1/polζ-dependent TLS inhibitors and validates the anti-cancer effects of combination cisplatin and TLS inhibitors. Our results demonstrate that TLS inhibitors do not have cell death-inducing activity on their own and may have additional inhibitory effects on cell proliferation and survival. TLS inhibitors indicate a strong promise for an effective and safe adjuvant agents for platinating agents in chemotherapy