The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non-Small Cell Lung Cancer

• Published in: Clinical cancer research Vol. 23; no. 18; pp. 5489 - 5501
• Main Authors: Cascone, Tina, Xu, Li, Lin, Heather Y, Liu, Wenbin, Tran, Hai T, Liu, Yuan, Howells, Kathryn, Haddad, Vincent, Hanrahan, Emer, Nilsson, Monique B, Cortez, Maria A, Giri, Uma, Kadara, Humam, Saigal, Babita, Park, Yun-Yong, Peng, Weiyi, Lee, Ju-Seog, Ryan, Anderson J, Jüergensmeier, Juliane M, Herbst, Roy S, Wang, Jing, Langley, Robert R, Wistuba, Ignacio I, Lee, Jack J, Heymach, John V
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.09.2017
• Subjects: Adenocarcinoma; Angiogenesis; Animal models; Animals; Biomarkers; Blood vessels; c-Met protein; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Clinical trials; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Models, Animal; DNA microarrays; Drug Resistance, Neoplasm - drug effects; Experimental design; Gene Expression Profiling; Hepatocyte growth factor; Hepatocyte Growth Factor - metabolism; Human performance; Humans; Hybridization; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Inhibition; Inhibitors; Kaplan-Meier Estimate; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Male; Mice; Microvasculature; Molecular Targeted Therapy; Multicenter Studies as Topic; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Non-small cell lung carcinoma; Patients; Plasma levels; Prognosis; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proto-Oncogene Proteins c-met - metabolism; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Signal Transduction; Signaling; Stroma; Tortuosity; Tumors; Tyrosine; Vascular endothelial growth factor receptors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3216

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. 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. 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. HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. .