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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Synthetic lethality has reshaped oncology, particularly in tumours with defects in DNA damage response (DDR) pathways, yet therapeutic strategies centred on canonical DDR targets, including poly(ADP-ribose) polymerase (PARP), ataxia telangiectasia and Rad3-related protein (ATR), checkpoint kinase 1 (CHK1) and Wee1 G2 checkpoint kinase (WEE1), remain constrained by resistance, toxicity and biological heterogeneity of DDR alterations. Emerging evidence indicates that DDR deficiency extends beyond impaired DNA repair to generate interconnected stress phenotypes involving replication fork instability, chromosomal instability, transcriptional and cell-cycle dysregulation, oxidative\/proteotoxic stress and metabolic imbalance. These states may increase tumour-cell reliance on kinases that are not canonical DNA repair enzymes or proximal DDR sensors, here referred to as non-canonical DDR-associated kinases. In this review, we examine the mechanistic rationale and translational potential of targeting kinases that regulate mitosis, transcriptional adaptation, checkpoint signalling, stress responses and metabolic homeostasis in DDR-defective tumours. We distinguish kinase dependencies supported by direct DDR-context-specific vulnerability or PARP inhibitor sensitisation from those whose relevance remains primarily mechanistic or hypothesis-generating and propose a shift from genotype-based patient selection toward functional stress phenotyping that integrates DNA repair capacity with replication stress, chromosomal instability, transcriptional conflict and the metabolic state. Finally, we evaluate pharmacological strategies, including rational combinations, allosteric modulation, polypharmacology and targeted protein degradation, and highlight the need for biomarker-guided clinical translation.<\/jats:p>","DOI":"10.3390\/ijms27188301","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding Synthetic Lethality in DNA Damage Response-Defective Cancers Through Stress Phenotype-Guided Kinase Targeting"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0919-5206","authenticated-orcid":false,"given":"Mirco","family":"Masi","sequence":"first","affiliation":[{"name":"Computational and Chemical Biology, Italian Institute of Technology (IIT), 16163 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Varignani","sequence":"additional","affiliation":[{"name":"Computational and Chemical Biology, Italian Institute of Technology (IIT), 16163 Genoa, Italy"},{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6370-1176","authenticated-orcid":false,"given":"Andrea","family":"Cavalli","sequence":"additional","affiliation":[{"name":"Computational and Chemical Biology, Italian Institute of Technology (IIT), 16163 Genoa, Italy"},{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"},{"name":"Centre Europ\u00e9en de Calcul Atomique et Mol\u00e9culaire (CECAM), Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-6675","authenticated-orcid":false,"given":"Stefania","family":"Girotto","sequence":"additional","affiliation":[{"name":"Structural Biophysics Facility, Italian Institute of Technology (IIT), 16163 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11488","DOI":"10.1021\/acs.jmedchem.4c00113","article-title":"New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives","volume":"67","author":"Previtali","year":"2024","journal-title":"J. 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