ArticleNature medicine2015
RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 184 papers.
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184 citing papers in PubMed, 276 citations in OpenAlex.
- Alectinib in combination with bevacizumab as first-line treatment in ALK-rearranged non-small cell lung cancer (ALEK-B): a single-arm, phase 2 trial.Nature communications · 2025Trial
- Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study.ESMO open · 2022Trial
- Invasive mucinous adenocarcinoma of the lung: integrating molecular landscape, imaging phenotypes, and translational therapeutic strategies.Translational lung cancer research · 2026Review
- Three decades of anaplastic lymphoma kinase: from physiological roles to cancer and immune evasion.Cancer metastasis reviews · 2026Review
- Risk Factors for Developing Venous Thromboembolism in Patients With Advanced ALK-Rearranged NSCLC.JTO clinical and research reports · 2026Article
- The novel ALK K1150dup mutation mediates resistance to frontline lorlatinib and retains sensitivity to gilteritinib.NPJ precision oncology · 2026Article
- Crizotinib attenuates bleomycin-induced pulmonary fibrosis via regulating fibroblast activation.Journal of thoracic disease · 2026Article
- Multiomics Profiling of T-cell Leukemia and Lymphoma Enables Targeted Therapeutic Discovery.Cancer research · 2026Article
- EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis.Cancer discovery · 2026Article
- Low-order assemblies drive oncogenic RTK fusion signaling without condensation.bioRxiv : the preprint server for biology · 2025Article
- Integration of Whole-Genome Sequencing Analysis with Unique Patient-Derived Models Reveals Clinically Relevant Drug Targets in TFCP2 Fusion-Defined Rhabdomyosarcoma.Molecular cancer therapeutics · 2025Article
- ALK-Targeted Therapy: Resistance Mechanisms and Emerging Precision Strategies.Current issues in molecular biology · 2025Review
- Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?International journal of molecular sciences · 2025Review
- BRAFbioRxiv : the preprint server for biology · 2025Article
- ALK in cancer: from function to therapeutic targeting.Nature reviews. Cancer · 2025Review
- RNase1-driven ALK-activation is an oncogenic driver and therapeutic target in non-small cell lung cancer.Signal transduction and targeted therapy · 2025Article
- Real time characterization of the MAPK pathway using native mass spectrometry.Communications biology · 2025Article
- Development of a reliable risk prognostic model for lung adenocarcinoma based on the genes related to endotheliocyte senescence.Scientific reports · 2025Article
- Article
- Long non-coding RNA CAR10 promotes angiogenesis of lung adenocarcinoma by mediating nuclear LDHA to epigenetically regulate VEGFA/C.Communications biology · 2025Article
124 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 6 institutions in 2 countries.
Funding
Abstract
One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.
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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.