ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Pharmacodynamic Response of the MET/HGF Receptor to Small-Molecule Tyrosine Kinase Inhibitors Examined with Validated, Fit-for-Clinic Immunoassays.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 34 citations in OpenAlex.
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- A Phase I Study of Nilotinib in Combination with Paclitaxel in Patients with Advanced Solid Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Savolitinib: A Promising Targeting Agent for Cancer.Cancers · 2023Review
- Overview of Molecular Detection Technologies forCancers · 2023Review
- Preserving the Phosphoproteome of Clinical Biopsies Using a Quick-Freeze Collection Device.Biopreservation and biobanking · 2022Article
- MET alterations in advanced pulmonary sarcomatoid carcinoma.Frontiers in oncology · 2022Review
- Combination therapy with pazopanib and tivantinib modulates VEGF and c-MET levels in refractory advanced solid tumors.Investigational new drugs · 2021Article
- Isoform- and Phosphorylation-specific Multiplexed Quantitative Pharmacodynamics of Drugs Targeting PI3K and MAPK Signaling in Xenograft Models and Clinical Biopsies.Molecular cancer therapeutics · 2021Article
- Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas.Oncotarget · 2020Article
- MET-dependent solid tumours - molecular diagnosis and targeted therapy.Nature reviews. Clinical oncology · 2020Review
- Clinical Evolution of Epithelial-Mesenchymal Transition in Human Carcinomas.Cancer research · 2020Observational
- System-based approaches as prognostic tools for glioblastoma.BMC cancer · 2019Review
- Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- The use of research biopsies in oncology trials: challenges and controversies.Journal of hospital management and health policy · 2019Article
- Failures in preclinical and clinical trials of c-Met inhibitors: evaluation of pathway activity as a promising selection criterion.Oncotarget · 2019Article
- HGF/c-MET Signaling in Melanocytes and Melanoma.International journal of molecular sciences · 2018Review
- What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?Journal of oncology practice · 2018Article
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
purposeRational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect. EXPERIMENTAL
designSandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models.
resultsBy limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation.
conclusionsThese validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683-94. ©2016 AACR.
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