biostudies-literatureParkhitko AALAM FoundationCancer Research UKBreast Cancer NowNIA NIH HHSIrish Research Council Laureate AwardsNational Cancer InstituteNCI NIH HHSNIGMS NIH HHSNational Institute on Aginge1009354https://www.ebi.ac.uk/biostudies/studies/S-EPMC7909629biostudies-literatureUnknown17(2)The RB1 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 RB1 could lead to new approaches to treating cancers with inactivated RB1. We identified 95 SL partners of RB1 based on a Drosophila screen for genetic modifiers of the eye phenotype caused by defects in the RB1 ortholog, Rbf1. We validated 38 mammalian orthologs of Rbf1 modifiers as RB1 SL partners in human cancer cell lines with defective RB1 alleles. We further show that for many of the RB1 SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of RB1 was associated with improvePLoS geneticsCross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells.PMC7909629244395P01CA120964NIA K99 AG05779214276K99 AG05779225237R01 GM084947R00 AG057792LAM00105E01-15P01 CA120964Hsieh SHannenhalli SRyan CJHu YLord CJPerrimon NParkhitko AASingh ABinari RfalseCross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells.The RB1 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 RB1 could lead to new approaches to treating cancers with inactivated RB1. We identified 95 SL partners of RB1 based on a Drosophila screen for genetic modifiers of the eye phenotype caused by defects in the RB1 ortholog, Rbf1. We validated 38 mammalian orthologs of Rbf1 modifiers as RB1 SL partners in human cancer cell lines with defective RB1 alleles. We further show that for many of the RB1 SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of RB1 was associated with improve2021-01-01T00:00:00Z2021 Feb2026-04-07T18:45:59.604Z2025-02-19T00:18:34.643ZS-EPMC79096293359198110.1371/journal.pgen.1009354