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Clin Cancer Res. 2017 Sep 15;23(18):5489-5501. doi: 10.1158/1078-0432.CCR-16-3216. Epub 2017 May 30.

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

Author information

1
Division of Cancer Medicine and Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
GlaxoSmithKline, Research Triangle Park, North Carolina and Collegeville, Pennsylvania.
5
AstraZeneca, Macclesfield, United Kingdom.
6
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
9
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Section of Medical Oncology and Department of Developmental Therapeutics, Yale School of Medicine, New Haven, Connecticut.
12
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Division of Cancer Medicine and Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jheymach@mdanderson.org.

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. Clin Cancer Res; 23(18); 5489-501. ©2017 AACR.

PMID:
28559461
PMCID:
PMC5600821
DOI:
10.1158/1078-0432.CCR-16-3216
[Indexed for MEDLINE]
Free PMC Article

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