Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer
Giorgia Maroni, Mahmoud A. Bassal, Indira Krishnan, Chee Wai Fhu, Virginia Savova, Rapolas Žilionis, Valerie A. Maymi, Nicole Pandell, Eva Csizmadia, Junyan Zhang, Barbara Storti, Julio Castaño, Riccardo Panella, Jia Li, Corinne E. Gustafson, Sam Fox, Rachel D. Levy, Claire V. Meyerovitz, Peter J. Tramontozzi, Kimberly Vermilya, Assunta De Rienzo, Stefania Crucitta, Daniela S. Daniela Sanchez Bassères, Marla Weetall, Art Branstrom, Alessandra Giorgetti, Raffaele Ciampi, Marzia Del Re, Romano Danesi, Ranieri Bizzarri, Henry Yang, Olivier Kocher, Allon M. Klein, Robert S. Welner, Raphael Bueno, Maria Cristina Magli, John G. Clohessy, Azhar Ali, Daniel G. Tenen, Elena Levantini
Abstract
Lung 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.