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MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat.
Chen, Jasmine; Guanizo, Aleks C; Jakasekara, W Samantha N; Inampudi, Chaitanya; Luong, Quinton; Garama, Daniel J; Alamgeer, Muhammad; Thakur, Nishant; DeVeer, Michael; Ganju, Vinod; Watkins, D Neil; Cain, Jason E; Gough, Daniel J.
Afiliación
  • Chen J; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Guanizo AC; Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Jakasekara WSN; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Inampudi C; Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Luong Q; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Garama DJ; Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Alamgeer M; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Thakur N; Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • DeVeer M; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Ganju V; Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Watkins DN; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Cain JE; Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
  • Gough DJ; Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Vic, 3168, Australia.
J Exp Clin Cancer Res ; 42(1): 100, 2023 Apr 26.
Article en En | MEDLINE | ID: mdl-37098540
BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance. METHODS: Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC. RESULTS: MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival. CONCLUSIONS: MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido