Department of Pharmaceutical Sciences, University of Connecticut , Storrs, CT, United States.
Expert Opin Investig Drugs. 2021 Jan;30(1):13-24. doi: 10.1080/13543784.2021.1850692. Epub 2020 Dec 3.
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. 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. 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.
跨损伤合成（TLS）是一种 DNA 损伤容忍机制，它用专门的、低保真度的 TLS DNA 聚合酶取代复制性 DNA 聚合酶，该酶可以在活跃的复制过程中复制过去的 DNA 损伤。最近的研究表明，TLS 在复制一线致遗传毒性药物诱导的过去的 DNA 损伤中起主要作用，导致疗效降低和获得化疗耐药性。考虑到这一点，将 TLS 作为一线致遗传毒性药物的联合策略的靶点已成为开发新型抗癌辅助药物的一种有前途的方法。在这篇综述中，我们简要介绍了 TLS 及其在癌症中的作用。我们还讨论了鉴定和开发针对各种 TLS DNA 聚合酶或 TLS 机制中的关键蛋白-蛋白相互作用（PPIs）的抑制剂。TLS 抑制剂已初步显示出前景；然而，为了更充分地了解这一新兴抗癌化疗药物的临床潜力，继续研究它们是至关重要的。确定参与 TLS 的特定蛋白质是否是最佳靶标非常重要。此外，更全面地了解哪些当前的致遗传毒性化疗药物与 TLS 抑制剂协同作用，将指导设计联合治疗的临床策略。
