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Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma.
Odeniyide, Patience; Yohe, Marielle E; Pollard, Kai; Vaseva, Angelina V; Calizo, Ana; Zhang, Lindy; Rodriguez, Fausto J; Gross, John M; Allen, Amy N; Wan, Xiaolin; Somwar, Romel; Schreck, Karisa C; Kessler, Linda; Wang, Jiawan; Pratilas, Christine A.
Afiliación
  • Odeniyide P; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Yohe ME; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Pollard K; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Vaseva AV; The Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
  • Calizo A; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Zhang L; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Rodriguez FJ; Department of Laboratory Medicine and Pathology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
  • Gross JM; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Allen AN; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Wan X; Division of Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Somwar R; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Schreck KC; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Kessler L; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Wang J; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Pratilas CA; Kura Oncology, San Diego, CA, USA.
Oncogene ; 41(21): 2973-2983, 2022 05.
Article en En | MEDLINE | ID: mdl-35459782
Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Rabdomiosarcoma / Rabdomiosarcoma Embrionario Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 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: Rabdomiosarcoma / Rabdomiosarcoma Embrionario Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido