Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencingin aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mu...

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Detalles Bibliográficos
Autores: Maroni, Giorgia, Bassal, Mahmoud A., Krishnan, Indira, Chee, Chee Wai, Savova, Virginia, Zilionis, Rapolas, Maymi, Valerie A., Pandell, Nicole, Csizmadia, Eva, Zhang, Junyan, Storti, Barbara, Castaño, Julio, Panella, Riccardo, Li, Jia, Gustafson, Corinne E., Fox, Sam, Levy, Rachel D., Meyerovitz, Claire V., Tramontozzi, Peter J., Vermilya, Kimberly, Rienzo, Assunta De, Crucitta, Stefania, Bassères, Daniela S., Weetall, Marla, Branstrom, Art, Giorgetti, Alessandra, Ciampi, Raffaele, Re, Marzia Del, Danesi, Romano, Bizzarri, Ranieri, Yang, Henry, Kocher, Olivier, Klein, Allon M., Welner, Robert S., Bueno, Raphael, Magli, Maria Cristina, Clohessy, John G., Ali, Azhar, Tenen, Daniel G., Levantini, Elena
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/177192
Acceso en línea:https://hdl.handle.net/2445/177192
Access Level:acceso abierto
Palabra clave:Càncer de pulmó
Mortalitat
Lung cancer
Mortality
Descripción
Sumario:Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencingin aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

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