DNA Repair Pathways & DDR

The DNA damage response (DDR) is defined as a coordinated cellular network responsible for the recognition, signaling, and repair of DNA damage. To safeguard cellular viability and genome integrity, cells employ sophisticated DDR mechanisms, including non-homologous end joining (NHEJ), homologous recombination (HR), mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER). Inhibition of the DDR is anticipated to impair DNA repair processes, leading to the accumulation of persistent unrepaired DNA breaks, disruption of cell cycle progression, and enhanced sensitization of cancer cells to diverse DNA-damaging agents such as chemotherapeutic drugs. Research conducted over the past two decades has synthesised and tested hundreds of small-molecule inhibitors targeting key DDR proteins (e.g., ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia-and-Rad3-related protein (ATR), Wee1, etc.), with some demonstrating antitumour activity in human cancers ^{[1] [3]}.

Currently, the development of novel DDR inhibitors and the exploration of combination therapy strategies are key research priorities. Wee1, a serine/threonine (Ser/Thr) protein kinase, serves as a critical regulator of cell cycle progression at the G2/M transition. Pharmacological inhibition of Wee1 abrogates this G2/M checkpoint, forcing cells to enter mitosis with damaged or under-replicated DNA. Several Wee1 inhibitors including Debio 0123, IMP7068, SC0191, and SY-4835 are currently undergoing solid tumor trials, with preliminary data showing promising results. In addition, distinct types of DDR inhibitors have been integrated into cancer treatment strategies, which include immunotherapy, chemotherapy, and radiotherapy, for the purpose of achieving combined therapeutic benefits ^{[1] [2] [4]}.

The application of DDR inhibitors in cancer treatment holds immense promise while presenting significant challenges. Key challenges include managing severe side effects such as leukopenia and bone marrow toxicity, particularly when these inhibitors are combined with chemotherapy. Future efforts must focus on enhancing the specificity of DDR inhibitors through improved drug design to overcome existing limitations. This could pave the way for their widespread adoption in cancer treatment regimens ^[3].