DDR targeted Therapies in oncology: Medical advances and emerging strategies

Abstract: Background: The DNA damage response (DDR) serves an essential cellular protective function, directing responses to damage caused to DNA in order to repair those lesions, and maintain genomic stability. Abnormalities in DDR pathways contribute to the development of tumors by inducing genomic instability and allowing mutations and resistance to therapies to accrue across numerous cancer types. Objective: This review discusses the dual function of DDR in cancer biology, as both a tumor suppressor and a therapeutic vulnerability, and recent advances in translation to promote therapeutic use of DDR pathways. Methods: Extensive review was performed on key DDR types and pathways, how they can be dysregulated in cancer, and treatment strategies that exploit such defects in DDR. The present review areas include mechanisms of synthetic lethality, drug development pipelines, resistance issues, and biomarker-driven precision oncology. Results: Defects in key DDR genes such as BRCA1/2, ATM, and p53 are common in different cancers. The identification and therapeutic targeting of these deficiencies using PARP inhibitors has revolutionized the treatment of BRCA-mutated cancers. New DDR-directed drugs (e.g., ATR, CHK1, and WEE1 inhibitors) are in different stages of clinical development. Combinations with immune checkpoint inhibitors such as anti-PD-1, and radiotherapy have shown promise and are advancing use. Nevertheless, resistance through restoration of genetic reversion, compensated repair pathways, and tumor heterogeneity continues to limit efficacy in clinical use. Emerging methodologies (e.g., CRISPR-based screening platforms, organoid models, and genomics-guided profiling), are improving the discovery of new DDR targets and predictive biomarkers.