Targeting the DNA damage response in cancer

Abstract

DNA damage response (DDR) pathway is the coordinated cellular network dealing with the identification, signaling, and repair of DNA damage. It tightly regulates cell cycle progression and promotes DNA repair to minimize DNA damage to daughter cells. Key proteins involved in DDR are frequently mutated/inactivated in human cancers and promote genomic instability, a recognized hallmark of cancer. Besides being an intrinsic property of tumors, DDR also represents a unique therapeutic opportunity. Indeed, inhibition of DDR is expected to delay repair, causing persistent unrepaired breaks, to interfere with cell cycle progression, and to sensitize cancer cells to several DNA-damaging agents, such as radiotherapy and chemotherapy. In addition, DDR defects in cancer cells have been shown to render these cells more dependent on the remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over the past two decades has led to the synthesis and testing of hundreds of small inhibitors against key DDR proteins, some of which have shown antitumor activity in human cancers. In parallel, the search for synthetic lethality interaction is broadening the use of DDR inhibitors. In this review, we discuss the state-of-art of ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 and Polθ inhibitors, highlighting the results obtained in the ongoing clinical trials both in monotherapy and in combination with chemotherapy and radiotherapy.

Keywords: ATM; ATR; Chk1; DNA damage response; Polθ; Wee1; solid tumors.

FIGURE 1

Schematic overview of the DNA damage response (DDR) pathway. The schematic activation of the DDR after single and double DNA strand breaks (SSB and DSB, respectively) is illustrated. As shown, the activation of ataxia‐telangiectasia mutated (ATM) and ataxia‐telangiectasia‐and‐Rad3‐related protein (ATR) lead to the downstream phosphorylation of checkpoint kinase 1/2 (Chk1/2) kinases that will activate downstream proteins leading to cell cycle arrest to facilitate repair. CDK, cyclin‐dependent kinase. The figure has been created by the authors using BioRender.

FIGURE 2

Schematic overview of the main DNA repair pathways. The figure summarizes the main DNA repair pathways. Base excision repair is involved in the repair of single strands, mismatch repair detects and repairs base mismatches resulting during replication, double strand breaks can be repaired by different pathways (homologous recombination, non‐homologous recombination and Polθ‐mediated end joining) with different degree of fidelity and bulky adducts and crosslinks require the nucleotide excision repair, involving more than 20 proteins. See text for a detailed explanation of these pathways. BER, base excision repair; BRCA1, breast cancer protein 1; BRCA2, breast cancer protein 2; DNAPKcs, DNA‐protein kinase catalytic subunit; DSBs, double strand breaks; LIG, ligase; MMR, mismatch repair; MRN complex, MRE11‐RAD50‐NBS1; PALB2, partner and localizer of BRCA2; PARP1, poly‐ADP‐ribose‐polymerase 1; PCNA, proliferating cell nuclear antigen; POL, polymerase; RPA, replication protein A; SSBs, single strand breaks; XPA, xeroderma pigmentosum, complementation group A; XRCC1, X‐ray repair cross‐complementing protein 1. The figure has been created by the authors using BioRender.

FIGURE 3

Repair of DNA double strand breaks. This type of damage can be repaired mainly by three pathways that have different initial processing (DNA end resection versus no resection) and are characterized by a different degree of fidelity, as shown in the figure. c‐NHEJ, classical‐non‐homologous‐end‐joining; DNAPKcs, DNA‐protein kinase catalytic subunit; HR, homologous recombination; POL, polymerase; TMEJ, polymerase theta‐mediated end joining. The figure has been created by the authors using BioRender.