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Authors: Deric L. Wheeler, Mar Iida, Tim J. Kruser, Meghan M. Nechrebecki, Emily F. Dunn, Eric A. Armstrong, Shyhmin Huang and Paul M. Harari

Deric L. Wheeler

Corresponding author: dlwheeler@wisc.edu
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Mar Iida

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Tim J. Kruser

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Meghan M. Nechrebecki

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Emily F. Dunn

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Eric A. Armstrong

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Shyhmin Huang

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Paul M. Harari

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Abstract:
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.

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