Translesion synthesis inhibitors as a new class of cancer chemotherapeutics

Introduction: Translesion synthesis (TLS) is a DNA damage tolerance mechanism that replaces the replicative DNA polymerase with a specialized, low-fidelity TLS DNA polymerase that can copy past DNA lesions during active replication. Recent studies have demonstrated a primary role for TLS in replicating past DNA lesions induced by first-line genotoxic agents, resulting in decreased efficacy and acquired chemoresistance. With this in mind, targeting TLS as a combination strategy with first-line genotoxic agents has emerged as a promising approach to develop a new class of anti-cancer adjuvant agents. Areas covered: In this review, we provide a brief background on TLS and its role in cancer. We also discuss the identification and development of inhibitors that target various TLS DNA polymerases or key protein-protein interactions (PPIs) in the TLS machinery. Expert opinion: TLS inhibitors have demonstrated initial promise; however, their continued study is essential to more fully understand the clinical potential of this emerging class of anti-cancer chemotherapeutics. It will be important to determine whether a specific protein involved in TLS is an optimal target. In addition, an expanded understanding of what current genotoxic chemotherapies synergize with TLS inhibitors will guide the clinical strategies for devising combination therapies.

Automated summary

Translesion synthesis (TLS) is a DNA damage tolerance mechanism that plays a primary role in replicating past DNA lesions induced by genotoxic agents in cancer. Inhibitors targeting various TLS DNA polymerases or key protein-protein interactions in the TLS machinery have shown promise as a new class of anti-cancer adjuvant agents. Further studies are needed to determine the clinical potential and optimal targets for TLS inhibitors in combination therapies with current genotoxic chemotherapies.