Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer
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Published:2021-04-14
Issue:1
Volume:4
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Maroni Giorgia, Bassal Mahmoud A.ORCID, Krishnan Indira, Fhu Chee Wai, Savova Virginia, Zilionis Rapolas, Maymi Valerie A., Pandell Nicole, Csizmadia Eva, Zhang Junyan, Storti Barbara, Castaño JulioORCID, Panella Riccardo, Li Jia, Gustafson Corinne E.ORCID, Fox Sam, Levy Rachel D., Meyerovitz Claire V., Tramontozzi Peter J., Vermilya Kimberly, De Rienzo Assunta, Crucitta Stefania, Bassères Daniela S., Weetall Marla, Branstrom Art, Giorgetti Alessandra, Ciampi Raffaele, Del Re Marzia, Danesi RomanoORCID, Bizzarri Ranieri, Yang Henry, Kocher Olivier, Klein Allon M.ORCID, Welner Robert S., Bueno Raphael, Magli Maria Cristina, Clohessy John G.ORCID, Ali Azhar, Tenen Daniel G.ORCID, Levantini ElenaORCID
Abstract
AbstractLung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in 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.
Funder
Regione Toscana NUS | Faculty of Science, National University of Singapore Beth Israel Deaconess Medical Center National University of Singapore PTC Therapeutics
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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