Tumor-specific subpopulation in KRAS-mutant NSCLC responds to anti-BMI-1 therapy

Lung cancer is a highly heterogeneous disease. Single cell RNA sequencing of lung cancer epithelial cells represents an undeveloped field. Here, we addressed aggressive KRAS-mutant murine and clinical lung cancers, by studying their heterogeneous subpopulations. At first, we resolved the unique subpopulations of healthy versus transgenic mutant Kras/null p53 adenocarcinoma-bearing lungs, identifying tumor-enriched subpopulations, of which one was almost exclusively detectable in tumors. Subsequently, we discovered that transformed epithelial cells express the oncogene BMI-1, which we targeted through PTC596, currently in clinical trial. BMI-1 inhibition decreased in vivo tumor growth in mice, and caused almost complete disappearance of the tumor-exclusive subpopulation. Deconvolution of clinical adenocarcinomas identified a BMI-1+ epithelial cluster selectively detectable in KRAS-mutant patients, which matches the mutant KRAS signature identified in the murine tumor-exclusive subpoulation. Our findings encourage development of anti-BMI-1-targeted therapies for NSCLC patients carrying KRAS mutations for which no pharmacological indication is available.