Inhibition of IGF1R enhances 2-deoxyglucose in the treatment of non-small cell lung cancer

• Type of Material: Article
• Authors: Fakeng Liu, Emory University; Yuan Liu, Emory University; Xiuju Liu, Emory University; Kaisheng Mao, Emory University; Diansheng Zhong, Tianjin Medical University; Adam Marcus, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University; Yulong He, Sun Yat-Sen University; Wei Zhou, Emory University
• Language: English
• Date: 2018-09-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier B.V. CC BY NC ND 4.0
• Final Published Version (URL): http://dx.doi.org/10.1016/j.lungcan.2018.06.026
• Title of Journal or Parent Work: Lung Cancer
• ISSN: 0169-5002
• Volume: 123
• Start Page: 36
• End Page: 43
• Grant/Funding Information: Funding was provided by grants to W.Z. (R01-CA203928, R01-CA140571); to A.I.M and W.Z (R01CA194027); to F.R.K (P01 CA116676); and to S.Y.S. (R01-CA160522) from the National Institute of Cancer; China Scholarship Council to F.L.; and Anise McDaniel Brock Scholar fund to W.Z.; This work was also supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University; and NIH/NCI under award number P30CA138292.
• Keywords: ENERGY-METABOLISM; BMS-754807; Science & Technology; PHOSPHORYLATION; Tumor suppressor gene; Insulin-Like growth factor receptor 1 (IGF1R); 2-DEOXY-D-GLUCOSE; Respiratory System; STRAND BREAK REPAIR; Oncology; EXPRESSION; Energy metabolism; Lung cancer; PATHWAYS; LKB1 TUMOR-SUPPRESSOR; Cancer therapy; Life Sciences & Biomedicine; ACTIVATION; APOPTOSIS
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Objective: We previously postulated that 2-deoxyglucose (2-DG) activates multiple pro-survival pathways through IGF1R to negate its inhibitory effect on glycolysis. Here, we evaluated whether IGF1R inhibitor synergizes with 2-DG to impede the growth of non-small cell lung cancer (NSCLC). Materials and methods: The activation of IGF1R signaling was assessed by the phosphorylation of IGF1R and its downstream target AKT using immunoblot. Drug dose response and combination index analyses were carried out according to the method of Chou and Talalay. Flow cytometry was used to evaluate cell cycle progression. Apoptosis was monitored by caspase-3/PARP cleavages or Annexin V staining. A subcutaneous xenograft model was used to assess this combination in vivo. Results: 2-DG induces the phosphorylation of IGF1R in its kinase domain, which can be abolished by the IGF1R inhibitor BMS-754807. Furthermore, the combination of 2-DG and BMS-754807 synergistically inhibited the survival of several non-small cell lung cancer (NSCLC) cell lines both in vitro and in vivo. The mechanistic basis of this synergy was cell line-dependent, and LKB1-inactivated EKVX cells underwent apoptosis following treatment with a subtoxic dose of 2-DG and BMS-754807. For these cells, the restoration of LKB1 kinase activity suppressed apoptosis induced by this combination but enhanced G1 arrest. In H460 cells, the addition of 2-DG did not enhance the low level of apoptosis induced by BMS-754807. However, treatment with 0.75 μM of BMS-754807 resulted in the accumulation of H460 cells with 8n-DNA content without affecting cell density increases. Hence, H460 cells may escape BMS-754807-induced G2/M cell cycle arrest through polyploidy. The inclusion of 2-DG blocked formation of the 8n-DNA cell population and restored G2/M phase cell cycle arrest. Conclusion: The combination of 2-DG and IGF1R inhibitor BMS-754807 may be used to suppress the proliferation of NSCLC tumors through different mechanisms.