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Pol\u03b8 is becoming a new target in cancer research because it demonstrates numerous synthetically lethal interactions with other DNA repair mechanisms, e.g., those involving PARP1, BRCA1\/2, DNA-PK, ATR. Inhibition of Pol\u03b8 could be achieved with different methods, such as RNA interference (RNAi), CRISPR\/Cas9 technology, or using small molecule inhibitors. In the context of this topic, RNAi and CRISPR\/Cas9 are still more often applied in the research itself rather than clinical usage, different than small molecule inhibitors. Several Pol\u03b8 inhibitors have been already generated, and two of them, novobiocin (NVB) and ART812 derivative, are being tested in clinical trials against HR-deficient tumors. In this review, we describe the significance of Pol\u03b8 and the Pol\u03b8-mediated TMEJ pathway. In addition, we summarize the current state of knowledge about Pol\u03b8 inhibitors and emphasize the promising role of Pol\u03b8 as a therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms24010319","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:40:39Z","timestamp":1672116039000},"page":"319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pol\u03b8 Inhibition: An Anticancer Therapy for HR-Deficient Tumours"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7191-3905","authenticated-orcid":false,"given":"Gabriela","family":"Barszczewska-Pietraszek","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-7993","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Drzewiecka","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5146-5225","authenticated-orcid":false,"given":"Piotr","family":"Czarny","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Skorski","sequence":"additional","affiliation":[{"name":"Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-7744","authenticated-orcid":false,"given":"Tomasz","family":"\u015aliwi\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nrc1691","article-title":"The concept of synthetic lethality in the context of anticancer therapy","volume":"5","author":"Kaelin","year":"2005","journal-title":"Nat. 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