The HGF/c-MET pathway is a driver and biomarker of VEGFR-inhibitor resistance and vascular remodeling in non–small cell lung cancer
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American Association for Cancer Research Inc.
Abstract
Purpose: Resistance to VEGFR inhibitors is a major obstacle in the treatment of non–small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors. Experimental Design: We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes. Results: Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In patients with cancer receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. Conclusions: HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. ©2017 AACR.
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Animals, Carcinoma, non-small-cell lung, Cell line, tumor, Clinical trials, phase ii as topic, Clinical trials, phase iii as topic, Disease models, animal, Drug resistance, neoplasm, Gene expression profiling, Hepatocyte growth factor, Humans, Hypoxia, Kaplan-meier estimate, Lung neoplasms, Male, Mice, Molecular targeted therapy, Multicenter studies as topic, Neovascularization, pathologic, Prognosis, Protein kinase inhibitors, Proto-oncogene proteins c-met, Receptors, vascular endothelial growth factor, Signal transduction, Xenograft model antitumor assays, Bevacizumab, Biological marker, Cabozantinib, Cediranib, Pazopanib, Scatter factor, Scatter factor receptor, Transcriptome, Unclassified drug, Vandetanib, Veg 102616, Hgf protein, human, Protein kinase inhibitor, Vasculotropin receptor, Animal cell, Animal experiment, Animal model, Animal tissue, Antineoplastic activity, Article, C met gene, Cancer cell, Cancer combination chemotherapy, Cancer inhibition, Cancer survival, Controlled study, Density, Drug efficacy, Drug sensitivity, Gene overexpression, Hgf gene, Human, Hybridization, Kidney metastasis, Lung adenocarcinoma, Microarray analysis, Microvascular density, Monotherapy, Mouse, Non small cell lung cancer, Nonhuman, Priority journal, Progression free survival, Protein expression, Protein protein interaction, Species difference, Treatment outcome, Tumor vascularization, Tumor xenograft, Vascular morphology, Vascular remodeling, Vascular resistance, Vessel tortuosity, Animal, Antagonists and inhibitors, Disease model, Drug effect, Drug resistance, Drug screening, Genetics, Kaplan meier method, Lung tumor, Metabolism, Molecularly targeted therapy, Multicenter study (topic), Neovascularization (pathology), Pathology, Phase 2 clinical trial (topic), Phase 3 clinical trial (topic), Tumor cell line