Your browser doesn't support javascript.
loading
SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
Wang, Zhentian; Hausmann, Simone; Lyu, Ruitu; Li, Tie-Mei; Lofgren, Shane M; Flores, Natasha M; Fuentes, Mary E; Caporicci, Marcello; Yang, Ze; Meiners, Matthew Joseph; Cheek, Marcus Adrian; Howard, Sarah Ann; Zhang, Lichao; Elias, Joshua Eric; Kim, Michael P; Maitra, Anirban; Wang, Huamin; Bassik, Michael Cory; Keogh, Michael-Christopher; Sage, Julien; Gozani, Or; Mazur, Pawel K.
Afiliação
  • Wang Z; Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • Hausmann S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lyu R; Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
  • Li TM; Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • Lofgren SM; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Flores NM; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Fuentes ME; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Caporicci M; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Yang Z; Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • Meiners MJ; EpiCypher Inc., Durham, NC 27709, USA.
  • Cheek MA; EpiCypher Inc., Durham, NC 27709, USA.
  • Howard SA; EpiCypher Inc., Durham, NC 27709, USA.
  • Zhang L; Chan Zuckenberg Biohub, Stanford, CA 94305, USA.
  • Elias JE; Chan Zuckenberg Biohub, Stanford, CA 94305, USA.
  • Kim MP; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Maitra A; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wang H; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Bassik MC; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Keogh MC; EpiCypher Inc., Durham, NC 27709, USA.
  • Sage J; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Gozani O; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu.
  • Mazur PK; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: pkmazur@mdanderson.org.
Cancer Cell ; 37(6): 834-849.e13, 2020 06 08.
Article em En | MEDLINE | ID: mdl-32442403
Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Cromatina / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Bibliotecas de Moléculas Pequenas / Terapia de Alvo Molecular / Metiltransferases Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Cromatina / Resistencia a Medicamentos Antineoplásicos / Inibidores de Proteínas Quinases / Bibliotecas de Moléculas Pequenas / Terapia de Alvo Molecular / Metiltransferases Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos