Advancing cancer therapy: new frontiers in targeting DNA damage response

Abstract

Genomic instability is a core characteristic of cancer, often stemming from defects in DNA damage response (DDR) or increased replication stress. DDR defects can lead to significant genetic alterations, including changes in gene copy numbers, gene rearrangements, and mutations, which accumulate over time and drive the clonal evolution of cancer cells. However, these vulnerabilities also present opportunities for targeted therapies that exploit DDR deficiencies, potentially improving treatment efficacy and patient outcomes. The development of PARP inhibitors like Olaparib has significantly improved the treatment of cancers with DDR defects (e.g., BRCA1 or BRCA2 mutations) based on synthetic lethality. This achievement has spurred further research into identifying additional therapeutic targets within the DDR pathway. Recent progress includes the development of inhibitors targeting other key DDR components such as DNA-PK, ATM, ATR, Chk1, Chk2, and Wee1 kinases. Current research is focused on optimizing these therapies by developing predictive biomarkers for treatment response, analyzing mechanisms of resistance (both intrinsic and acquired), and exploring the potential for combining DDR-targeted therapies with chemotherapy, radiotherapy, and immunotherapy. This article provides an overview of the latest advancements in targeted anti-tumor therapies based on DDR and their implications for future cancer treatment strategies.

Keywords: DNA damage response; genomic instability; resistance; synthetic lethality; vulnerability.

FIGURE 1

Overview of DNA Damage Response (DDR) Mechanisms Ensuring Cellular Viability and Genome Integrity. This figure illustrates the sophisticated network of DDR mechanisms that cells employ to maintain genome integrity. Central to the DDR are five key pathways: Non-Homologous End Joining (NHEJ), Homologous Recombination (HR), Mismatch Repair (MMR), Nucleotide Excision Repair (NER), and Base Excision Repair (BER). Each pathway is depicted with its specific role and interaction within the cellular environment to repair various types of DNA damage (created with BioRender.com, accessed on 25 August 2024).

FIGURE 2

Targeting Overexpressed DNA Repair Proteins in Cancer Therapy. This figure details the critical proteins in cancer cells central to DNA repair mechanisms, contributing to treatment resistance. Highlighted proteins include PARP, DNA-PKcs, ATM, ATR, Wee1 and Chk1/2, which enhance DNA repair and contribute to treatment resistance. The diagram also shows inhibitors developed to disrupt these pathways, depicting how each inhibitor interacts with its target protein to increase cancer cell sensitivity to treatments and potentially overcome resistance (created with BioRender.com, accessed on 25 August 2024).