ArticleMolecular oncology2015
KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- Vacuolar Protein Sorting 35 Controls Hepatocellular Proliferation Through SRC Signaling and Promotes Diethyl Nitrosamine-Induced Tumor Initiation.Cellular and molecular gastroenterology and hepatology · 2026Article
- The Preclinical Pharmacology of Tepotinib-A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations.Molecular cancer therapeutics · 2023Review
- The effects of mutant Ras proteins on the cell signalome.Cancer metastasis reviews · 2020Review
- Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement.Frontiers in cell and developmental biology · 2020Review
- Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma.Cell death & disease · 2019Article
- Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer.Cancers · 2019Article
- Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2019Article
- Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis.Molecular cancer therapeutics · 2019Article
- A Comparative Analysis of Individual RAS Mutations in Cancer Biology.Frontiers in oncology · 2019Review
- Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia.Oncogene · 2018Article
- RAS-MAPK Reactivation Facilitates Acquired Resistance inMolecular cancer therapeutics · 2018Article
- Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2018Article
- PIK3CA hotspot mutations differentially impact responses to MET targeting in MET-driven and non-driven preclinical cancer models.Molecular cancer · 2017Article
- MEK inhibitors against MET-amplified non-small cell lung cancer.International journal of oncology · 2016Article
- Importance of the type I insulin-like growth factor receptor in HER2, FGFR2 and MET-unamplified gastric cancer with and without Ras pathway activation.Oncotarget · 2016Article
- KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET-expressing tumor cells.Molecular oncology · 2015Article
- Performance of probe polymerization-conjunction-agarose gel electrophoresis in the rapid detection of KRAS gene mutation.Genetics and molecular biologyArticle
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The MET receptor tyrosine kinase is often deregulated in human cancers and several MET inhibitors are evaluated in clinical trials. Similarly to EGFR, MET signals through the RAS-RAF-ERK/MAPK pathway which plays key roles in cell proliferation and survival. Mutations of genes encoding for RAS proteins, particularly in KRAS, are commonly found in various tumors and are associated with constitutive activation of the MAPK pathway. It was shown for EGFR, that KRAS mutations render upstream EGFR inhibition ineffective in EGFR-positive colorectal cancers. Currently, there are no clinical studies evaluating MET inhibition impairment due to RAS mutations. To test the impact of RAS mutations on MET targeting, we generated tumor cells responsive to the MET inhibitor EMD1214063 that express KRAS G12V, G12D, G13D and HRAS G12V variants. We demonstrate that these MAPK-activating RAS mutations differentially interfere with MET-mediated biological effects of MET inhibition. We report increased residual ERK1/2 phosphorylation indicating that the downstream pathway remains active in presence of MET inhibition. Consequently, RAS variants counteracted MET inhibition-induced morphological changes as well as anti-proliferative and anchorage-independent growth effects. The effect of RAS mutants was reversed when MET inhibition was combined with MEK inhibitors AZD6244 and UO126. In an in vivo mouse xenograft model, MET-driven tumors harboring mutated RAS displayed resistance to MET inhibition. Taken together, our results demonstrate for the first time in details the role of KRAS and HRAS mutations in resistance to MET inhibition and suggest targeting both MET and MEK as an effective strategy when both oncogenic drivers are expressed.
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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.