Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells


Autoři: Andrey A. Parkhitko aff001;  Arashdeep Singh aff003;  Sharon Hsieh aff004;  Yanhui Hu aff001;  Richard Binari aff001;  Christopher J. Lord aff006;  Sridhar Hannenhalli aff003;  Colm J. Ryan aff007;  Norbert Perrimon aff001
Působiště autorů: Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff002;  Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff003;  Department of Biology, Boston University, Boston, Massachusetts, United States of America aff004;  Howard Hughes Medical Institute, Boston, Massachusetts, United States of America aff005;  CRUK Gene Function Laboratory, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom aff006;  Systems Biology Ireland, University College Dublin, Dublin, Ireland aff007;  School of Computer Science, University College Dublin, Dublin, Ireland aff008
Vyšlo v časopise: Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells. PLoS Genet 17(2): e1009354. doi:10.1371/journal.pgen.1009354
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009354

Souhrn

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 improved patient survival. We investigated higher order combinatorial gene interactions by creating a novel Drosophila cancer model with co-occurring Rbf1, Pten and Ras 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 RB1-deficient cells that may be further adapted for the treatment of human cancer.

Klíčová slova:

Breast cancer – Prostate cancer – Drosophila melanogaster – Eyes – Gastrointestinal cancers – Genetic screens – Lung and intrathoracic tumors – RNA interference


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