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Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition.
Augert, Arnaud; Eastwood, Emily; Ibrahim, Ali H; Wu, Nan; Grunblatt, Eli; Basom, Ryan; Liggitt, Denny; Eaton, Keith D; Martins, Renato; Poirier, John T; Rudin, Charles M; Milletti, Francesca; Cheng, Wei-Yi; Mack, Fiona; MacPherson, David.
Afiliación
  • Augert A; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
  • Eastwood E; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
  • Ibrahim AH; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
  • Wu N; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
  • Grunblatt E; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
  • Basom R; Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.
  • Liggitt D; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
  • Eaton KD; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
  • Martins R; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
  • Poirier JT; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Rudin CM; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Milletti F; Pharmaceutical Research and Early Development, Roche Innovation Center, New York, NY 10016, USA.
  • Cheng WY; Pharmaceutical Research and Early Development, Roche Innovation Center, New York, NY 10016, USA.
  • Mack F; Pharmaceutical Research and Early Development, Roche Innovation Center, New York, NY 10016, USA.
  • MacPherson D; Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA. dmacpher@fredhutch.org.
Sci Signal ; 12(567)2019 02 05.
Article en En | MEDLINE | ID: mdl-30723171
Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the NOTCH1 locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001-induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Ensayos Antitumor por Modelo de Xenoinjerto / Inhibidores Enzimáticos / Receptores Notch / Carcinoma Pulmonar de Células Pequeñas / Histona Demetilasas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Ensayos Antitumor por Modelo de Xenoinjerto / Inhibidores Enzimáticos / Receptores Notch / Carcinoma Pulmonar de Células Pequeñas / Histona Demetilasas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos