AXL regulates neuregulin1 expression leading to cetuximab resistance in head and neck cancer

Mari Iida, Nellie K. McDaniel, Kourtney L. Kostecki, Noah B. Welke, Carlene A. Kranjac, Peng Liu, Colin Longhurst, Justine Y. Bruce, Seungpyo Hong, Ravi Salgia, Deric L. Wheeler

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Background: The receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR) is overexpressed and an important therapeutic target in Head and Neck cancer (HNC). Cetuximab is currently the only EGFR-targeting agent approved by the FDA for treatment of HNC; however, intrinsic and acquired resistance to cetuximab is a major problem in the clinic. Our lab previously reported that AXL leads to cetuximab resistance via activation of HER3. In this study, we investigate the connection between AXL, HER3, and neuregulin1 (NRG1) gene expression with a focus on understanding how their interdependent signaling promotes resistance to cetuximab in HNC. Methods: Plasmid or siRNA transfections and cell-based assays were conducted to test cetuximab sensitivity. Quantitative PCR and immunoblot analysis were used to analyze gene and protein expression levels. Seven HNC patient-derived xenografts (PDXs) were evaluated for protein expression levels. Results: We found that HER3 expression was necessary but not sufficient for cetuximab resistance without AXL expression. Our results demonstrated that addition of the HER3 ligand NRG1 to cetuximab-sensitive HNC cells leads to cetuximab resistance. Further, AXL-overexpressing cells regulate NRG1 at the level of transcription, thereby promoting cetuximab resistance. Immunoblot analysis revealed that NRG1 expression was relatively high in cetuximab-resistant HNC PDXs compared to cetuximab-sensitive HNC PDXs. Finally, genetic inhibition of NRG1 resensitized AXL-overexpressing cells to cetuximab. Conclusions: The results of this study indicate that AXL may signal through HER3 via NRG1 to promote cetuximab resistance and that targeting of NRG1 could have significant clinical implications for HNC therapeutic approaches.

Original languageEnglish
Article number447
JournalBMC cancer
Issue number1
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
Research reported in this publication was supported, in part, by the Wisconsin Head & Neck Cancer SPORE (DLW, JYB P50 DE026787), an NIH grant from the Cellular and Molecular Pathology Graduate Training Program (NKM, 5 T32 GM81061-7), a pilot grant from the UW Institute for Clinical and Translational Research (ICTR) and the UW Carbone Cancer Center (DLW, ICTR-UWCH RD 12), and a University of Wisconsin Carbone Cancer Center Support Grant (P30 CA014520). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The authors thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP) supported by the UW Department of Pathology and the Office of the Director-NIH (S10OD023526) for use of its facilities and services.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Genetics
  • Cancer Research


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