@Article{or.2026.081879,
AUTHOR = {Kannan Sridharan, Ondrej Fiala, Gowri Sivaramakrishnan, Mimma Rizzo, Matteo Santoni},
TITLE = {Overcoming the Shield: Mechanisms of Resistance to DNA Repair Inhibitors and Strategies to Restore Synthetic Lethality},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/27361},
ISSN = {1555-3906},
ABSTRACT = {The emergence of resistance to poly (ADP-ribose) polymerase (PARP) inhibitors poses a significant obstacle in treating cancers characterized by BReast CAncer gene (<i>BRCA</i>) mutations or homologous recombination deficiency. Despite the substantial clinical benefits brought by drugs such as olaparib, niraparib, and talazoparib, a substantial proportion of tumors ultimately develop resistance. The underlying mechanisms are diverse and include the reconstitution of homologous recombination via secondary BRCA reversion mutations, stabilization of replication forks, enhanced drug efflux mediated by p-glycoproteins, and structural or functional alterations in PARP1 itself. A thorough grasp of these resistance pathways is critical for the design of effective therapeutic interventions. Emerging strategies aimed at countering resistance involve combinatorial regimens incorporating inhibitors of Ataxia telangiectasia and Rad3-related (ATR), WEE1, checkpoint kinase 1 (CHK1), or immune checkpoint blockade, and other agents that target DNA damage response (DDR) networks. Furthermore, next-generation PARP inhibitors and optimized drug scheduling paradigms are under investigation to reestablish tumor sensitivity. Refined, biomarker-guided patient selection and advanced molecular surveillance may further optimize treatment outcomes and postpone the onset of resistance. This review offers a mechanism-centric synthesis of resistance to DNA repair inhibitors and the therapeutic strategies being developed to circumvent it.},
DOI = {10.32604/or.2026.081879}
}