ArticleJCI insight2021
Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS-mutant lung cancer.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The trial behind it
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- The Role of KRAS in Non-Small Cell Lung Cancer: From Molecular Background to Precision Medicine.International journal of molecular sciences · 2026Review
- Transient p53/p21 activation selectively protects healthy human hair follicles and their stem cells from chemotherapy.The Journal of clinical investigation · 2026Article
- Emerging Strategies to Inhibit the G1/S Transition for Cancer Therapy.Cancer research · 2026Review
- Single-cell sequencing reveals the functional heterogeneity of melanoma cells and their crosstalk with the tumor microenvironment.Frontiers in genetics · 2026Article
- Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer.Frontiers in oncology · 2024Review
- Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti-PD-1 resistance in non-small cell lung cancer.The Journal of clinical investigation · 2023Article
- Impad1 and Syt11 work in an epistatic pathway that regulates EMT-mediated vesicular trafficking to drive lung cancer invasion and metastasis.Cell reports · 2022Article
- Cyclin-dependent kinases in breast cancer: expression pattern and therapeutic implications.Medical oncology (Northwood, London, England) · 2022Review
- A Breakthrough Brought about by Targeting KRASCancers · 2022Review
- Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors.Frontiers in oncology · 2022Article
- Non-genetic adaptive resistance to KRASFrontiers in oncology · 2022Review
- KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMTFrontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.