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SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers.
Shi, Lei; Shen, William; Davis, Mindy I; Kong, Ke; Vu, Phuong; Saha, Supriya K; Adil, Ramzi; Kreuzer, Johannes; Egan, Regina; Lee, Tobie D; Greninger, Patricia; Shrimp, Jonathan H; Zhao, Wei; Wei, Ting-Yu; Zhou, Mi; Eccleston, Jason; Sussman, Jonathan; Manocha, Ujjawal; Weerasekara, Vajira; Kondo, Hiroshi; Vijay, Vindhya; Wu, Meng-Ju; Kearney, Sara E; Ho, Jeffrey; McClanaghan, Joseph; Murchie, Ellen; Crowther, Giovanna S; Patnaik, Samarjit; Boxer, Matthew B; Shen, Min; Ting, David T; Kim, William Y; Stanger, Ben Z; Deshpande, Vikram; Ferrone, Cristina R; Benes, Cyril H; Haas, Wilhelm; Hall, Matthew D; Bardeesy, Nabeel.
Afiliação
  • Shi L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Shen W; The Cancer Program, Broad Institute, Cambridge, MA, USA.
  • Davis MI; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Kong K; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Vu P; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Saha SK; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Adil R; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Kreuzer J; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Egan R; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Lee TD; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Greninger P; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Shrimp JH; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Zhao W; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Wei TY; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Zhou M; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Eccleston J; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Sussman J; Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Manocha U; Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Weerasekara V; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Kondo H; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Vijay V; The Cancer Program, Broad Institute, Cambridge, MA, USA.
  • Wu MJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Kearney SE; The Cancer Program, Broad Institute, Cambridge, MA, USA.
  • Ho J; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • McClanaghan J; The Cancer Program, Broad Institute, Cambridge, MA, USA.
  • Murchie E; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Crowther GS; The Cancer Program, Broad Institute, Cambridge, MA, USA.
  • Patnaik S; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Boxer MB; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Shen M; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Ting DT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Kim WY; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Stanger BZ; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Deshpande V; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Ferrone CR; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • Benes CH; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Haas W; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Hall MD; Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Bardeesy N; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Nat Cancer ; 4(3): 365-381, 2023 03.
Article em En | MEDLINE | ID: mdl-36914816
ABSTRACT
Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Alquilantes / Neoplasias Hepáticas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Nat Cancer Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Alquilantes / Neoplasias Hepáticas Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Nat Cancer Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos