@article{10.1172/jci.insight.148392, author = {Aparna Padhye AND Jessica M. Konen AND B. Leticia Rodriguez AND Jared J. Fradette AND Joshua K. Ochieng AND Lixia Diao AND Jing Wang AND Wei Lu AND Luisa S. Solis AND Harsh Batra AND Maria G. Raso AND Michael D. Peoples AND Rosalba Minelli AND Alessandro Carugo AND Christopher A. Bristow AND Don L. Gibbons}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS-mutant lung cancer}, year = {2021}, month = {9}, volume = {6}, url = {https://insight.jci.org/articles/view/148392}, abstract = {Lack of sustained response to therapeutic agents in patients with KRAS-mutant lung cancer poses a major challenge and arises partly due to intratumor heterogeneity that defines phenotypically distinct tumor subpopulations. To attain better therapeutic outcomes, it is important to understand the differential therapeutic sensitivities of tumor cell subsets. Epithelial-mesenchymal transition is a biological phenomenon that can alter the state of cells along a phenotypic spectrum and cause transcriptional rewiring to produce distinct tumor cell subpopulations. We utilized functional shRNA screens, in in vitro and in vivo models, to identify and validate an increased dependence of mesenchymal tumor cells on cyclin-dependent kinase 4 (CDK4) for survival, as well as a mechanism of resistance to MEK inhibitors. High zinc finger E-box binding homeobox 1 levels in mesenchymal tumor cells repressed p21, leading to perturbed CDK4 pathway activity. Increased dependence on CDK4 rendered mesenchymal cancer cells particularly vulnerable to selective CDK4 inhibitors. Coadministration of CDK4 and MEK inhibitors in heterogeneous tumors effectively targeted different tumor subpopulations, subverting the resistance to either single-agent treatment.}, number = {17}, doi = {10.1172/jci.insight.148392}, url = {https://doi.org/10.1172/jci.insight.148392}, }