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

癌症研究 间质细胞 肝细胞生长因子 肺癌 凡德他尼 医学 癌症 受体酪氨酸激酶 肿瘤微环境 血管生成 血管通透性 酪氨酸激酶抑制剂 酪氨酸激酶 生物 病理 内科学 受体
作者
Tina Cascone,Li Xu,Heather Lin,Wenbin Liu,Hai T. Tran,Yuan Liu,Kathryn Howells,Vincent Haddad,Emer O. Hanrahan,Monique B. Nilsson,María Angélica Cortez,Uma Giri,Humam Kadara,Babita Saigal,Yun‐Yong Park,Weiyi Peng,Ju‐Seog Lee,Anderson J. Ryan,Juliane M. Jüergensmeier,Roy S. Herbst
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:23 (18): 5489-5501 被引量:70
标识
DOI:10.1158/1078-0432.ccr-16-3216
摘要

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.
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