ArticleNature medicine2012
Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia.
Article in Nature medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed, 183 citations in OpenAlex.
- C-MET tyrosine kinase receptor: mechanisms, clinical applications and future perspectives in cancer therapy.Signal transduction and targeted therapy · 2026Review
- Hepatocyte growth factor/c-Met signaling axis in human diseases: Mechanistic insights and therapeutic potential.Journal of cell communication and signaling · 2026Review
- Micro-RNA-140-3p Acts as a Tumor Suppressor Gene in Acute Promyelocytic Leukemia by Targeting Hepatocyte Growth Factor.Cell biochemistry and biophysics · 2025Article
- AnNational science review · 2025Article
- HGF/c-MET axis contributes to CLL cell survival by regulating multiple mechanisms making it a potential therapeutic target for CLL treatment.Frontiers in pharmacology · 2025Article
- The Prognostic Significance and Co-Expression of Fibroblast Growth Factor Receptor 2 and c-Met in Endometrial Cancer.International journal of women's health · 2025Article
- Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment.International journal of molecular sciences · 2024Review
- Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy.Cancer discovery · 2024Article
- Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation.Cancers · 2024Review
- Foretinib Is Effective in Acute Myeloid Leukemia by Inhibiting FLT3 and Overcoming Secondary Mutations That Drive Resistance to Quizartinib and Gilteritinib.Cancer research · 2024Article
- Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer.Cellular and molecular life sciences : CMLS · 2024Article
- Ferroptosis-Related Gene Signature for Prognosis Prediction in Acute Myeloid Leukemia and Potential Therapeutic Options.International journal of general medicine · 2024Article
- Review
- Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system.Biomaterials research · 2023Article
- Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7.Frontiers in cardiovascular medicine · 2023Review
- Oncogenic Signalling of Growth Factor Receptors in Cancer: Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2022Article
- The c-MET receptor tyrosine kinase contributes to neutrophil-driven pathology in cutaneous leishmaniasis.PLoS pathogens · 2022Article
- Cholesterol Regulates the Tumor Adaptive Resistance to MAPK Pathway Inhibition.Journal of proteome research · 2021Article
- Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.Leukemia · 2021Article
51 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 12 institutions in 3 countries.
Funding
Abstract
Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.
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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.