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Am J Cancer Res. 2017 Apr 1;7(4):831-844. eCollection 2017.

Targeting NRASQ61K mutant delays tumor growth and angiogenesis in non-small cell lung cancer.

Author information

1
Department of Interventional Radiology, Cangzhou Central Hospital of Hebei ProvinceNo.16, Xinhua West Road, Yunhe District, Cangzhou, Hebei, China.
2
Department of Magnetic Resonance Imaging, Cangzhou Central Hospital of Hebei ProvinceNo.16, Xinhua West Road, Yunhe District, Cangzhou, Hebei, China.

Abstract

Tumor cells require vascular supply for their growth, and they express proangiogenic growth factors that promote the formation of vascular networks. Many oncogenic mutations that may potentially lead to tumor angiogenesis have been identified. Somatic mutations in the small GTPase NRAS are the most common activating lesions found in human cancer and are generally associated with poor response to standard therapies. However, the mechanisms by which NRAS mutations affect tumor angiogenesis are largely unknown. Therefore, we investigated the role of NRASQ61K oncogene in tumor angiogenesis and analyzed tumors harboring NRASQ61K for potential sensitivity to a kinase inhibitor. Knock-in of the NRASQ61K allele in human normal epithelial cells triggered the angiogenic response in these cells. In cancer cells harboring oncogenic NRAS, a mitogen-activated protein kinase (MEK) inhibitor down-regulated the extracellular regulated protein kinase (ERK) pathway and inhibited the expression of proangiogenic molecules. In tumor xenografts harboring the NRASQ61K, the MEK inhibitor extensively modified tumor growth, causing abrogation of angiogenesis. Overall, our results provide a functional link between oncogenic NRAS and angiogenesis, and imply that tumor vasculature could be indirectly altered by targeting a genetic lesion on which cancer cells are dependent.

KEYWORDS:

NRAS; NSCLC; angiogenesis

PMID:
28469956
PMCID:
PMC5411791

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