{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T20:41:56Z","timestamp":1767732116279,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009354","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000}}],"reference-count":101,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T00:00:00Z","timestamp":1613433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["NIA K99 AG057792"],"award-info":[{"award-number":["NIA K99 AG057792"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005963","name":"LAM Foundation","doi-asserted-by":"publisher","award":["LAM00105E01-15"],"award-info":[{"award-number":["LAM00105E01-15"]}],"id":[{"id":"10.13039\/100005963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"crossref","award":["5P01CA120964"],"award-info":[{"award-number":["5P01CA120964"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Irish Research Council Laureate Awards"},{"name":"Breast Cancer Now"},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    The\n                    <jats:italic>RB1<\/jats:italic>\n                    tumor suppressor is recurrently mutated in a variety of cancers including retinoblastomas, small cell lung cancers, triple-negative breast cancers, prostate cancers, and osteosarcomas. Finding new synthetic lethal (SL) interactions with\n                    <jats:italic>RB1<\/jats:italic>\n                    could lead to new approaches to treating cancers with inactivated\n                    <jats:italic>RB1<\/jats:italic>\n                    . We identified 95 SL partners of\n                    <jats:italic>RB1<\/jats:italic>\n                    based on a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    screen for genetic modifiers of the eye phenotype caused by defects in the\n                    <jats:italic>RB1<\/jats:italic>\n                    ortholog,\n                    <jats:italic>Rbf1<\/jats:italic>\n                    . We validated 38 mammalian orthologs of\n                    <jats:italic>Rbf1<\/jats:italic>\n                    modifiers as RB1 SL partners in human cancer cell lines with defective\n                    <jats:italic>RB1<\/jats:italic>\n                    alleles. We further show that for many of the\n                    <jats:italic>RB1<\/jats:italic>\n                    SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of\n                    <jats:italic>RB1<\/jats:italic>\n                    was associated with improved patient survival. We investigated higher order combinatorial gene interactions by creating a novel\n                    <jats:italic>Drosophila<\/jats:italic>\n                    cancer model with co-occurring\n                    <jats:italic>Rbf1<\/jats:italic>\n                    ,\n                    <jats:italic>Pten<\/jats:italic>\n                    and\n                    <jats:italic>Ras<\/jats:italic>\n                    mutations, and found that targeting RB1 SL genes in this background suppressed the dramatic tumor growth and rescued fly survival whilst having minimal effects on wild-type cells. Finally, we found that drugs targeting the identified RB1 interacting genes\/pathways, such as UNC3230, PYR-41, TAK-243, isoginkgetin, madrasin, and celastrol also elicit SL in human cancer cell lines. In summary, we identified several high confidence, evolutionarily conserved, novel targets for\n                    <jats:italic>RB1-<\/jats:italic>\n                    deficient cells that may be further adapted for the treatment of human cancer.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009354","type":"journal-article","created":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T17:31:45Z","timestamp":1613496705000},"page":"e1009354","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9852-8329","authenticated-orcid":true,"given":"Andrey 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