Pre-clinical characterization of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, combined with ionizing radiation for head and neck squamous cell carcinoma.
Epidermal growth factor receptor (EGFR) is over-expressed in nearly all cases of squamous cell carcinoma of the head and neck (SCCHN), and is an important driver of disease progression. EGFR targeted therapies have demonstrated clinical benefit for SCCHN treatment. In this report, we investigated the pre-clinical efficacy of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, both alone and in combination with ionizing radiation (IR), a primary curative modality for SCCHN. One normal oral epithelial (NOE) and three SCCHN (FaDu, UT-SCC-8, UT-SCC-42a) cell lines were used to conduct cell viability, clonogenic survival, cell cycle, and immunoblotting assays in vitro, using increasing doses of Dacomitinib (10-500 nM), both with and without IR (2-4 Gy). The FaDu xenograft model was utilized for tumor growth delay assays in vivo, and immunohistochemical analyses were conducted on extracted tumors. A dose-dependent reduction in cell viability and clonogenic survival after Dacomitinib treatment was observed in all three SCCHN models. Treatment led to a significant reduction in EGFR signalling, with a subsequent decrease in phosphorylation of downstream targets such as ERK, AKT, and mTOR. In vivo, Dacomitinib treatment delayed tumor growth, while decreasing phospho-EGFR and Ki-67 immunoexpression. These effects were further enhanced when combined with IR, both in vitro and in vivo. The preclinical data support the further evaluations of Dacomitinib combined with IR for the future management of patients with SCCHN.
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Justin P
JP
Williams
Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
Inki
I
Kim
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Emma
E
Ito
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Wei
W
Shi
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Shijun
S
Yue
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada; Division of Medical Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
Lillian L
LL
Siu
Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
John
J
Waldron
Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
Brian
B
O'Sullivan
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Kenneth W
KW
Yip
Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
Fei-Fei
FF
Liu
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
D052999:Quinazolinones; C525726:dacomitinib; D066246:ErbB Receptors