Maroni G, Bassal MA, Krishnan I, Fhu CW, Savova V, Zilionis R, Maymi VA, Pandell N, Csizmadia E, Zhang J, Storti B, Castaño J, Panella R, Li J, Gustafson CE, Fox S, Levy RD, Meyerovitz CV, Tramontozzi PJ, Vermilya K, De Rienzo A, Crucitta S, Bassères DS, Weetall M, Branstrom A, Giorgetti A, Ciampi R, Del Re M, Danesi R, Bizzarri R, Yang H, Kocher O, Klein AM, Welner RS, Bueno R, Magli MC, Clohessy JG, Ali A, Tenen DG, Levantini E.
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Harvard Medical School, Boston, MA, USA.
3Institute of Biomedical Technologies, National Research Council (CNR), Area della Ricerca di Pisa, Pisa, Italy.
4Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
5Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
6Beth Israel Deaconess Medical Center, Boston, MA, USA.
7Preclinical Murine Pharmacogenetics Core, Beth Israel Deaconess Cancer Center, Dana Farber/Harvard Cancer Center, Boston, MA, USA.
8NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, Pisa, Italy.
9Platform for Immunotherapy BST-Hospital Clinic, Banc de Sang i Teixits (BST), Barcelona, Spain.
10Center for Genomic Medicine, Desert Research Institute, Reno, NV, USA.
11Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women’s Hospital, Boston, MA, USA.
12Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
13Biochemistry Department, Chemistry Institute, University of Sao Paulo, Sao Paulo, Brazil.
14PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ, USA.
15Cell Biology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
16Stem Cell Biology and Leukemiogenesis Group, Regenerative Medicine Program, Institut d’Investigació Biomèdica de Bellvitge – IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain.
17Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.
18Unit of Clinical Pharmacology and Pharmacogenetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
19Department of Surgical, Medical and Molecular Pathology, and Critical Care Medicine, University of Pisa, Pisa, Italy.
20University of Alabama at Birmingham, Department of Medicine, Hemathology/Oncology, Birmingham, AL, USA.
21Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. daniel.tenen@nus.edu.sg.
22Harvard Medical School, Boston, MA, USA. daniel.tenen@nus.edu.sg.
23Harvard Stem Cell Institute, Cambridge, MA, USA. daniel.tenen@nus.edu.sg.
24Harvard Medical School, Boston, MA, USA. elevanti@bidmc.harvard.edu.
25Institute of Biomedical Technologies, National Research Council (CNR), Area della Ricerca di Pisa, Pisa, Italy. elevanti@bidmc.harvard.edu.
26Beth Israel Deaconess Medical Center, Boston, MA, USA. elevanti@bidmc.harvard.edu.
27Harvard Stem Cell Institute, Cambridge, MA, USA. elevanti@bidmc.harvard.edu.
#Contributed equally.
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.