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Splice-switch oligonucleotide-based combinatorial platform prioritizes synthetic lethal targets CHK1 and BRD4 against MYC-driven hepatocellular carcinoma.
Thng, Dexter Kai Hao; Toh, Tan Boon; Pigini, Paolo; Hooi, Lissa; Dan, Yock Young; Chow, Pierce Kah-Hoe; Bonney, Glenn Kunnath; Rashid, Masturah Bte Mohd Abdul; Guccione, Ernesto; Wee, Dave Keng Boon; Chow, Edward Kai-Hua.
Afiliación
  • Thng DKH; Cancer Science Institute of Singapore, National University of Singapore Singapore Singapore.
  • Toh TB; The N.1 Institute for Health, National University of Singapore Singapore Singapore.
  • Pigini P; The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore Singapore.
  • Hooi L; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (ASTAR) Singapore Singapore.
  • Dan YY; Cancer Science Institute of Singapore, National University of Singapore Singapore Singapore.
  • Chow PK; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore.
  • Bonney GK; Cancer Science Institute of Singapore, National University of Singapore Singapore Singapore.
  • Rashid MBMA; Division of Gastroenterology and Hepatology National University Health System Singapore Singapore.
  • Guccione E; Department of Medicine, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore.
  • Wee DKB; Division of Surgical Oncology National Cancer Centre Singapore Singapore Singapore.
  • Chow EK; Department of Hepato-Pancreato-Biliary and Transplant Surgery Singapore General Hospital Singapore Singapore.
Bioeng Transl Med ; 8(1): e10363, 2023 Jan.
Article en En | MEDLINE | ID: mdl-36684069
ABSTRACT
Deregulation of MYC is among the most frequent oncogenic drivers in hepatocellular carcinoma (HCC). Unfortunately, the clinical success of MYC-targeted therapies is limited. Synthetic lethality offers an alternative therapeutic strategy by leveraging on vulnerabilities in tumors with MYC deregulation. While several synthetic lethal targets of MYC have been identified in HCC, the need to prioritize targets with the greatest therapeutic potential has been unmet. Here, we demonstrate that by pairing splice-switch oligonucleotide (SSO) technologies with our phenotypic-analytical hybrid multidrug interrogation platform, quadratic phenotypic optimization platform (QPOP), we can disrupt the functional expression of these targets in specific combinatorial tests to rapidly determine target-target interactions and rank synthetic lethality targets. Our SSO-QPOP analyses revealed that simultaneous attenuation of CHK1 and BRD4 function is an effective combination specific in MYC-deregulated HCC, successfully suppressing HCC progression in vitro. Pharmacological inhibitors of CHK1 and BRD4 further demonstrated its translational value by exhibiting synergistic interactions in patient-derived xenograft organoid models of HCC harboring high levels of MYC deregulation. Collectively, our work demonstrates the capacity of SSO-QPOP as a target prioritization tool in the drug development pipeline, as well as the therapeutic potential of CHK1 and BRD4 in MYC-driven HCC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bioeng Transl Med Año: 2023 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bioeng Transl Med Año: 2023 Tipo del documento: Article
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