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An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.
Hagenbeek, Thijs J; Zbieg, Jason R; Hafner, Marc; Mroue, Rana; Lacap, Jennifer A; Sodir, Nicole M; Noland, Cameron L; Afghani, Shervin; Kishore, Ayush; Bhat, Kamakoti P; Yao, Xiaosai; Schmidt, Stephen; Clausen, Saundra; Steffek, Micah; Lee, Wendy; Beroza, Paul; Martin, Scott; Lin, Eva; Fong, Rina; Di Lello, Paola; Kubala, Marta H; Yang, Michelle N-Y; Lau, Jeffrey T; Chan, Emily; Arrazate, Alfonso; An, Le; Levy, Elizabeth; Lorenzo, Maria N; Lee, Ho-June; Pham, Trang H; Modrusan, Zora; Zang, Richard; Chen, Yi-Chen; Kabza, Michal; Ahmed, Musaddeque; Li, Jason; Chang, Matthew T; Maddalo, Danilo; Evangelista, Marie; Ye, Xin; Crawford, James J; Dey, Anwesha.
Afiliación
  • Hagenbeek TJ; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Zbieg JR; Department of Discovery Chemistry, Genentech, California, CA, USA.
  • Hafner M; Department of Oncology Bioinformatics, Genentech, California, CA, USA.
  • Mroue R; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Lacap JA; Department of Translational Oncology, Genentech, California, CA, USA.
  • Sodir NM; Department of Translational Oncology, Genentech, California, CA, USA.
  • Noland CL; Department of Structural Biology, Genentech, California, CA, USA.
  • Afghani S; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Kishore A; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Bhat KP; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Yao X; Department of Oncology Bioinformatics, Genentech, California, CA, USA.
  • Schmidt S; Department of Biochemical and Cellular Pharmacology, Genentech, California, CA, USA.
  • Clausen S; Department of Biochemical and Cellular Pharmacology, Genentech, California, CA, USA.
  • Steffek M; Department of Biochemical and Cellular Pharmacology, Genentech, California, CA, USA.
  • Lee W; Department of Discovery Chemistry, Genentech, California, CA, USA.
  • Beroza P; Department of Discovery Chemistry, Genentech, California, CA, USA.
  • Martin S; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Lin E; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Fong R; Department of Structural Biology, Genentech, California, CA, USA.
  • Di Lello P; Department of Structural Biology, Genentech, California, CA, USA.
  • Kubala MH; Department of Structural Biology, Genentech, California, CA, USA.
  • Yang MN; Department of Translational Oncology, Genentech, California, CA, USA.
  • Lau JT; Department of Translational Oncology, Genentech, California, CA, USA.
  • Chan E; Department of Translational Oncology, Genentech, California, CA, USA.
  • Arrazate A; Department of Translational Oncology, Genentech, California, CA, USA.
  • An L; Department of Small Molecule Pharmaceutical Sciences, Genentech, California, CA, USA.
  • Levy E; Department of Small Molecule Pharmaceutical Sciences, Genentech, California, CA, USA.
  • Lorenzo MN; Department of Protein Chemistry, Genentech, California, CA, USA.
  • Lee HJ; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Pham TH; Department of Discovery Oncology, Genentech, California, CA, USA.
  • Modrusan Z; Department of Microchemistry, Proteomics and Lipidomics, Genentech, California, CA, USA.
  • Zang R; Department of Drug Metabolism and Pharmacokinetics, Genentech, California, CA, USA.
  • Chen YC; Department of Drug Metabolism and Pharmacokinetics, Genentech, California, CA, USA.
  • Kabza M; Roche Polska, Warsaw, Poland.
  • Ahmed M; Roche Canada, Mississauga, Ontario, Canada.
  • Li J; Department of Oncology Bioinformatics, Genentech, California, CA, USA.
  • Chang MT; Department of Oncology Bioinformatics, Genentech, California, CA, USA.
  • Maddalo D; Department of Translational Oncology, Genentech, California, CA, USA.
  • Evangelista M; Department of Discovery Oncology, Genentech, California, CA, USA. evangem2@gmail.com.
  • Ye X; Department of Discovery Oncology, Genentech, California, CA, USA. ye.xin@gene.com.
  • Crawford JJ; Department of Discovery Chemistry, Genentech, California, CA, USA. crawford.james@gene.com.
  • Dey A; Department of Discovery Oncology, Genentech, California, CA, USA. dey.anwesha@gene.com.
Nat Cancer ; 4(6): 812-828, 2023 06.
Article en En | MEDLINE | ID: mdl-37277530
The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas p21(ras) / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas p21(ras) / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido