ArticleProceedings of the National Academy of Sciences of the United States of America2018
Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. 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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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Non-surgical Synergistic Interventions for the Treatment of Skin Cancer.Current pharmaceutical design · 2026Review
- Bioactive Products Targeting C-Met As Potential Antitumour Drugs.Anti-cancer agents in medicinal chemistry · 2025Review
- An Observatory for theCancers · 2023Review
- Case report: targeted sequencing improves the diagnosis of multiple synchronous lung cancers.Translational lung cancer research · 2023Article
- Integrated proteogenomic characterization of medullary thyroid carcinoma.Cell discovery · 2022Article
- Efficacy of CAR-T immunotherapy in MET overexpressing tumors not eligible for anti-MET targeted therapy.Journal of experimental & clinical cancer research : CR · 2022Article
- hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of 'MET-addicted' cancers.Journal of experimental & clinical cancer research : CR · 2022Article
- Durable Response of Dabrafenib, Trametinib, and Capmatinib in an NSCLC Patient With Co-Existing BRAF-KIAA1549 Fusion and MET Amplification: A Case Report.Frontiers in oncology · 2022Article
- Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies.Medical oncology (Northwood, London, England) · 2021Review
- Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer.Molecular cancer therapeutics · 2021Article
- When the MET receptor kicks in to resist targeted therapies.Oncogene · 2021Review
- Targeted Sequencing Facilitated Diagnosis of an Uncommon Patient Harboring Both Multiple Primary and Intrapulmonary Metastatic Lung Cancer: A Case Report.OncoTargets and therapy · 2021Article
- The AKT-independent MET-V-ATPase-MTOR axis suppresses liver cancer vaccination.Signal transduction and targeted therapy · 2020Article
- A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.Nature communications · 2020Article
- Use of Fluorescence In Situ Hybridization (FISH) in Diagnosis and Tailored Therapies in Solid Tumors.Molecules (Basel, Switzerland) · 2020Review
- Fast fluorescence in situ hybridisation for the enhanced detection of MET in non-small cell lung cancer.PloS one · 2019Article
- ARQ-197 enhances the antitumor effect of sorafenib in hepatocellular carcinoma cells via decelerating its intracellular clearance.OncoTargets and therapy · 2019Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer clonal evolution is based on accrual of driving genetic alterations that are expected to cooperate and progressively increase malignancy. Little is known on whether any genetic alteration can hinder the oncogenic function of a coexisting alteration, so that therapeutic targeting of the one can, paradoxically, revive the function of the other. We report the case of a driver oncogene (MET) that is not only bypassed, but also disabled by the mutation of a downstream transducer (BRAF), and reignited by inhibition of the latter. In a metastasis originated from a cancer of unknown primary (CUP), the MET oncogene was amplified eightfold, but unexpectedly, the kinase was dephosphorylated and inactive. As result, specific drugs targeting MET (JNJ-38877605) failed to inhibit growth of xenografts derived from the patient. In addition to MET amplification, the patient harbored, as sole proliferative driver, a mutation hyperactivating BRAF (G469A). Surprisingly, specific blockade of the BRAF pathway was equally ineffective, and it was accompanied by rephosphorylation of the amplified MET oncoprotein and by revived addiction to MET. Mechanistically, MET inactivation in the context of the BRAF-activating mutation is driven through a negative feedback loop involving inactivation of PP2A phosphatase, which in turn leads to phosphorylation on MET inhibitory Ser985. Disruption of this feedback loop allows PP2A reactivation, removing the inhibitory phosphorylation from Ser985 and thereby unleashing MET kinase activity. Evidence is provided for a mechanism of therapeutic resistance to single-oncoprotein targeting, based on reactivation of a genetic alteration functionally dormant in targeted cancer cells.
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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.