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

Aparna Padhye,Maria G Raso,Joshua K Ochieng,Jing Wang,Wei Lu,Harsh Batra,Alessandro Carugo,Rosalba Minelli,Jared J Fradette,Christopher A Bristow,B Leticia Rodriguez,Lixia Diao,Luisa S Solis,Michael D Peoples,Don L Gibbons,Jessica M Konen

doi:10.1172/jci.insight.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.

Highlights

Activating KRAS mutation is one of the most frequent oncogenic events in lung cancer, occurring in about 30% of patients with lung adenocarcinoma [1,2,3]
We demonstrate that lung tumors with high ZEB1 that display mesenchymal phenotype have increased dependence on cyclin-dependent kinase 4 (CDK4) pathway for survival, which renders them especially vulnerable to CDK4 inhibitors
Combined with our previously published results that showed higher sensitivity of epithelial cancer cells to MEK inhibitors [11], we investigated the combination of CDK4 and MEK inhibitors in multiple preclinical models that recapitulate epithelial-mesenchymal transition (EMT)-mediated tumor heterogeneity and demonstrated this as an effective strategy to combat heterogeneity and resistance

Summary

Introduction

Activating KRAS mutation is one of the most frequent oncogenic events in lung cancer, occurring in about 30% of patients with lung adenocarcinoma [1,2,3]. Despite the identification of the oncogene over 20 years ago and significant efforts to treat this subset of patients, 5-year survival rates remain dismal [4]. Combination of MEK inhibitors with conventional chemotherapy did not demonstrate any added benefit to progression-free survival [8]. Resistance to MEK inhibitors may be intrinsic (de novo) due to tumor cell heterogeneity or acquired due to tumor evolution as an adaptive response to pharmacological agents. We need to understand the differences in the tumor cell subpopulations within a heterogeneous tumor

Methods

Results

Conclusion