Andrew M Baschnagel1, Sandra Galoforo2, Bryan J Thibodeau3, Samreen Ahmed3, Sonali Nirmal3, Jan Akervall4, George D Wilson5. 1. Department of Human Oncology, Universtiy of Wisconsin, Carbone Cancer Center, Madison, WI, U.S.A. 2. Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, U.S.A. 3. Beaumont BioBank, William Beaumont Hospital, Royal Oak, MI, U.S.A. 4. Beaumont BioBank, William Beaumont Hospital, Royal Oak, MI, U.S.A. Department of Otolaryngology, William Beaumont Hospital, Royal Oak, MI, U.S.A. 5. Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI, U.S.A. Beaumont BioBank, William Beaumont Hospital, Royal Oak, MI, U.S.A. George.Wilson@beaumont.edu.
Abstract
AIM: Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. MATERIALS AND METHODS: Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. RESULTS: All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UT-SCC-15 tumors grown as xenografts. CONCLUSION: MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model. Copyright
AIM: Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. MATERIALS AND METHODS: Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. RESULTS: All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UT-SCC-15 tumors grown as xenografts. CONCLUSION: MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model. Copyright
Authors: George D Wilson; Thomas G Wilson; Alaa Hanna; Mohamad Dabjan; Katie Buelow; John Torma; Brian Marples; Sandra Galoforo Journal: Clin Transl Radiat Oncol Date: 2020-11-08
Authors: Andrew M Baschnagel; Saakshi Kaushik; Arda Durmaz; Steve Goldstein; Irene M Ong; Lindsey Abel; Paul A Clark; Zafer Gurel; Ticiana Leal; Darya Buehler; Gopal Iyer; Jacob G Scott; Randall J Kimple Journal: Sci Rep Date: 2021-01-28 Impact factor: 4.379