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Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy.
Quintanal-Villalonga, Alvaro; Taniguchi, Hirokazu; Hao, Yuan; Chow, Andrew; Zhan, Yingqian A; Chavan, Shweta S; Uddin, Fathema; Allaj, Viola; Manoj, Parvathy; Shah, Nisargbhai S; Chan, Joseph M; Offin, Michael; Ciampricotti, Metamia; Ray-Kirton, Jordana; Egger, Jacklynn; Bhanot, Umesh; Linkov, Irina; Asher, Marina; Roehrl, Michael H; Qiu, Juan; de Stanchina, Elisa; Hollmann, Travis J; Koche, Richard P; Sen, Triparna; Poirier, John T; Rudin, Charles M.
Afiliación
  • Quintanal-Villalonga A; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York. quintaa1@mskcc.org john.poirier@nyulangone.org rudinc@mkcc.org.
  • Taniguchi H; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hao Y; Perlmutter Cancer Center, New York University Langone Health, New York, New York.
  • Chow A; Applied Bioinformatics Laboratories, NYU School of Medicine, New York, New York.
  • Zhan YA; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Chavan SS; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Uddin F; Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Allaj V; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Manoj P; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Shah NS; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Chan JM; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Offin M; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Ciampricotti M; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Ray-Kirton J; Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Egger J; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Bhanot U; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Linkov I; Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Asher M; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Roehrl MH; Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Qiu J; Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
  • de Stanchina E; Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hollmann TJ; Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Koche RP; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Sen T; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Poirier JT; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Rudin CM; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Res ; 82(3): 472-483, 2022 02 01.
Article en En | MEDLINE | ID: mdl-34815254
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease. SIGNIFICANCE: CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Citoplasmáticos y Nucleares / Carioferinas / Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Citoplasmáticos y Nucleares / Carioferinas / Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos