Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS mutant lung cancer

Abstract Lack of sustained response to therapeutic agents in patients with K-Ras 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-to-mesenchymal transition (EMT) is a biologic phenomenon that can alter the phenotypic state and cause transcriptional rewiring to produce distinct tumor cell populations. We utilized functional shRNA screens, in vitro and in vivo models to identify and confirm an increased dependence of mesenchymal tumor cells on CDK4 for survival, as well as a mechanism of resistance to MEK inhibitors. High ZEB1 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. Co-administration of CDK4 and MEK inhibitors in heterogeneous tumors effectively targeted different tumor subpopulations, subverting the resistance to either single agent treatment.