Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I-specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7. FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg.
Highlights
Lung cancer is a leading cause of cancer-related deaths worldwide, and non–small cell lung cancer (NSCLC) represents approximately 85% of all cases of lung cancer [1]
Targeted therapies based on EGF receptor (EGFR)activating mutations and EML4-ALK gene rearrangements have become standard therapeutic tools, and this approach has resulted in the extension of survival rates for patients with NSCLCs [2]
Mutations in F-box and WD-40 domain protein 7 gene (FBXW7) and a low copy number of FBXW7 have been reported to be associated with low levels of FBXW7 expression and with resistance to antitubulin chemotherapeutics via accumulation of MCL1 [5]. These findings indicate that FBXW7 plays very important roles in cancer progression and refractory disease in NSCLCs
Summary
Lung cancer is a leading cause of cancer-related deaths worldwide, and non–small cell lung cancer (NSCLC) represents approximately 85% of all cases of lung cancer [1]. Targeted therapies based on EGF receptor (EGFR)activating mutations and EML4-ALK gene rearrangements have become standard therapeutic tools, and this approach has resulted in the extension of survival rates for patients with NSCLCs [2]. Patients with advanced NSCLCs who would not respond to a targeted therapy have poor prognoses. To improve the prognosis in patients with NSCLCs, further research is required worldwide to identify new therapeutic targets. We focused on the F-box and WD-40 domain protein 7 gene (FBXW7), which encodes a tumor. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Authors' Affiliation: Departments of General Surgical Science, Graduate School of Medicine, Gunma University, Showamachi, Maebashi, Japan
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