biostudies-literatureMaroni GNational University of SingaporeBeth Israel Deaconess Medical CenterPTC TherapeuticsNHLBI NIH HHSRegione ToscanaNUS | Faculty of Science, National University of SingaporeNCI NIH HHS370https://www.ebi.ac.uk/biostudies/studies/S-EPMC8046784biostudies-literatureUnknown4(1)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.Communications biologyIdentification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer.PMC8046784Chief Academic Award CAO 2015Jax Pilot Award (BIDMC/Jax)P01 CA066996sponsored research supportR713-000-216-720Bando FAS Salute 2014R35 CA197697P01 HL131477R33 CA212697Yong Siew Research Grant WBS R713-001-013-271R01 CA218579Storti BBranstrom ABueno RCrucitta SFhu CWDe Rienzo AZhang JBasseres DSMeyerovitz CVCiampi RBizzarri RDel Re MTenen DGCsizmadia EWelner RSAli ADanesi RMagli MCMaroni GLevy RDGustafson CEYang HKocher OBassal MALi JPandell NSavova VCastano JLevantini EMaymi VAPanella RFox SKlein AMVermilya KKrishnan ITramontozzi PJGiorgetti AWeetall MClohessy JGZilionis RfalseIdentification 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 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.2021-01-01T00:00:00Z2021 Apr2024-11-14T05:01:38.509Z2022-02-10T08:20:51.743ZS-EPMC80467843385416810.1038/s42003-021-01897-6