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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00013

Survivin in insulin-like growth factor-induced resistance to lapatinib in head and neck squamous carcinoma cells

 Christine E. Lehman1, Rolando E. Mendez1, Michael I. Dougherty1, Amir Allak1,  Oluwayemisis L. Adejumo1, Linnea E. Taniguchi1,  Ashraf Khalil1, 2, Daniel G. Gioeli1 and  Mark J. Jameson1*
  • 1Department of Head and Neck Oncologic and Microvascular Surgery, University of Virginia Health System, United States
  • 2Department of Biochemistry, National Liver Institute, Egypt

Epidermal growth factor receptor (EGFR) inhibitors have limited efficacy in head and neck squamous cell carcinoma (HNSCC) due to various resistance mechanisms, such as activation of the insulin-like growth factor-1 receptor (IGF1R), which initiates pro-survival signaling. Survivin, a member of the inhibitor of apoptosis proteins family, is expressed at relatively high levels in malignant tissues and plays a role in cell division. Expression of survivin in tumors has been shown to correlate with poor prognosis due to chemotherapy resistance and anti-apoptotic behavior. We previously demonstrated that activation of the IGF1R reduces sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) via reduced apoptosis suggesting a role of survivin in this process. This study evaluates the role of survivin in IGF1R-mediated lapatinib resistance. Using HNSCC cell lines FaDu and SCC25, survivin expression increased and lapatinib sensitivity decreased with IGF1R activation. Further, these effects were reversed by the survivin inhibitor YM-155. Conversely, survivin expression and lapatinib sensitivity were unchanged with IGF1R activation in UNC10 cells. YM-155 enhanced the inhibitory effect of lapatinib on UNC10 cells, regardless of activation of the IGF1R. These results demonstrate that enhanced survivin expression correlates with IGF1R-mediated lapatinib resistance in HNSCC cells and suggest that regulation of survivin expression may be a key mechanistic element in IGF1R-based therapeutic resistance. Combinatorial treatment with survivin antagonists and EGFR-TKIs warrants further investigation.

Keywords: survivin, IGF1R, lapatinib, HNSCC (head and neck squamous cell carcinoma), Resistance

Received: 08 Aug 2018; Accepted: 03 Jan 2019.

Edited by:

Dietmar Thurnher, Medical University of Graz, Austria

Reviewed by:

Thorsten Fuereder, Medical University of Vienna, Austria
Thomas J. Ow, Montefiore Medical Center, United States  

Copyright: © 2019 Lehman, Mendez, Dougherty, Allak, Adejumo, Taniguchi, Khalil, Gioeli and Jameson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mark J. Jameson, University of Virginia Health System, Department of Head and Neck Oncologic and Microvascular Surgery, Charlottesville, Virginia, United States,