Receptor tyrosine kinase MET as potential target of multi-kinase inhibitor and radiosensitizer sorafenib in HNSCC
Kaweh Beizaei
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorLisa Gleißner MS
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorKonstantin Hoffer
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorLara Bußmann MD
Department of Otorhinolaryngology and Head and Neck Surgery, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorAnh Thu Vu
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorLeonhard Steinmeister MD
Department for Diagnostic and Interventional Radiology and Nuclear Medicine, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorSimon Laban MD
Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Ulm, Ulm, Germany
Search for more papers by this authorNikolaus Möckelmann MD
Department of Otorhinolaryngology and Head and Neck Surgery, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorAdrian Münscher MD
Department of Otorhinolaryngology and Head and Neck Surgery, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorCordula Petersen MD
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorKai Rothkamm PhD
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorCorresponding Author
Malte Kriegs PhD
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Correspondence
Malte Kriegs, Laboratory of Radiobiology and Experimental Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg D-20246, Germany.
Email: [email protected]
Search for more papers by this authorKaweh Beizaei
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorLisa Gleißner MS
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorKonstantin Hoffer
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorLara Bußmann MD
Department of Otorhinolaryngology and Head and Neck Surgery, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorAnh Thu Vu
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorLeonhard Steinmeister MD
Department for Diagnostic and Interventional Radiology and Nuclear Medicine, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorSimon Laban MD
Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Ulm, Ulm, Germany
Search for more papers by this authorNikolaus Möckelmann MD
Department of Otorhinolaryngology and Head and Neck Surgery, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorAdrian Münscher MD
Department of Otorhinolaryngology and Head and Neck Surgery, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorCordula Petersen MD
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorKai Rothkamm PhD
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Search for more papers by this authorCorresponding Author
Malte Kriegs PhD
Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum—University Cancer Center Hamburg, Hamburg-Eppendorf, Germany
Correspondence
Malte Kriegs, Laboratory of Radiobiology and Experimental Radiation Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg D-20246, Germany.
Email: [email protected]
Search for more papers by this authorAbstract
Background
The multi-kinase inhibitor sorafenib displays antitumoral effects in head and neck squamous cell carcinoma (HNSCC); however, the targeted kinases are unknown. Here we aimed to identify those kinases to determine the mechanism of sorafenib-mediated effects and establish candidate biomarkers for patient stratification.
Methods
The effects of sorafenib and MET inhibitors crizotinib and SU11274 were analyzed using a slide-based antibody array, Western blotting, proliferation, and survival assays. X-rays were used for irradiations.
Results
Sorafenib inhibited auto-phosphorylation of epidermal growth factor receptor and MET, which has not been described previously. MET expression in HNSCC cells was not always associated with activity/phosphorylation. Furthermore, sorafenib-dependent cell kill and radiosensitization was not associated with MET level. Although MET inhibitors blocked proliferation, they caused only mild cytotoxicity and no radiosensitization.
Conclusion
We identified MET as a new potential target of sorafenib. However, MET inhibition is not the cause for sorafenib-mediated cytotoxicity or radiosensitization.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of interest with the contents of this article.
Supporting Information
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Appendix S1 Supporting Information. |
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REFERENCES
- 1Mockelmann N, Kriegs M, Lorincz BB, Busch CJ, Knecht R. Molecular targeting in combination with platinum-based chemoradiotherapy in head and neck cancer treatment. Head Neck. 2015; 38: E2173-E2181.
- 2Laban S, Steinmeister L, Gleissner L, et al. Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation. Radiother Oncol. 2013; 109(2): 286-292.
- 3Mockelmann N, Rieckmann T, Busch CJ, et al. Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells. Oncotarget. 2016; 7(17): 23542-23551.
- 4Gleissner L, Kwiatkowski M, Myllynen L, et al. Analyzing the influence of kinase inhibitors on DNA repair by differential proteomics of chromatin-interacting proteins and nuclear phospho-proteins. Oncotarget. 2017; 8(67): 110983-110993.
- 5Dai XF, Ding J, Zhang RG, Ren JH, Ma CM, Wu G. Radiosensitivity enhancement of human hepatocellular carcinoma cell line SMMC-7721 by sorafenib through the MEK/ERK signal pathway. Int J Radiat Biol. 2013; 89(9): 724-731.
- 6Heravi M, Tomic N, Liang L, et al. Sorafenib in combination with ionizing radiation has a greater anti-tumour activity in a breast cancer model. Anticancer Drugs. 2012; 23(5): 525-533.
- 7Kuo YC, Lin WC, Chiang IT, et al. Sorafenib sensitizes human colorectal carcinoma to radiation via suppression of NF-kappaB expression in vitro and in vivo. Biomed Pharmacother. 2012; 66(1): 12-20.
- 8Yadav A, Kumar B, Teknos TN, Kumar P. Sorafenib enhances the antitumor effects of chemoradiation treatment by downregulating ERCC-1 and XRCC-1 DNA repair proteins. Mol Cancer Ther. 2011; 10(7): 1241-1251.
- 9Riedel M, Struve N, Muller-Goebel J, et al. Sorafenib inhibits cell growth but fails to enhance radio- and chemosensitivity of glioblastoma cell lines. Oncotarget. 2016; 7(38): 61988-61995.
- 10Williamson SK, Moon J, Huang CH, et al. Phase II evaluation of sorafenib in advanced and metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group Study S0420. J Clin Oncol. 2010; 28(20): 3330-3335.
- 11Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007; 25(24): 3766-3773.
- 12Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006; 24(5): 736-747.
- 13Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006; 5(10): 835-844.
- 14Kriegs M, Kasten-Pisula U, Riepen B, et al. Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests. Oncotarget. 2016; 7(29): 45122-45133.
- 15Cui JJ, Tran-Dube M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011; 54(18): 6342-6363.
- 16Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013; 368(25): 2385-2394.
- 17Sattler M, Pride YB, Ma P, et al. A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res. 2003; 63(17): 5462-5469.
- 18Yang H, Lee HW, Kim Y, et al. Radiosensitization of brain metastasis by targeting c-MET. Lab Invest. 2013; 93(3): 344-353.
- 19Li Y, Wang J, Gao X, et al. C-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation. PLoS One. 2014; 9(11): e113186.
- 20Lal B, Xia S, Abounader R, Laterra J. Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation. Clin Cancer Res. 2005; 11(12): 4479-4486.
- 21Baschnagel AM, Galoforo S, Thibodeau BJ, et al. Crizotinib fails to enhance the effect of radiation in head and neck squamous cell carcinoma Xenografts. Anticancer Res. 2015; 35(11): 5973-5982.
- 22Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001; 37(Suppl 4): S9-S15.
- 23Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010; 11(12): 834-848.
- 24Baschnagel AM, Williams L, Hanna A, et al. C-Met expression is a marker of poor prognosis in patients with locally advanced head and neck squamous cell carcinoma treated with chemoradiation. Int J Radiat Oncol Biol Phys. 2014; 88(3): 701-707.
- 25Hartmann S, Bhola NE, Grandis JR. HGF/Met signaling in head and neck cancer: impact on the tumor microenvironment. Clin Cancer Res. 2016; 22(16): 4005-4013.
- 26Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002; 62(24): 7350-7356.
- 27Kim EH, Kim MS, Jung WG. The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells. Oncol Rep. 2014; 32(6): 2421-2428.
- 28Harari PM, Allen GW, Bonner JA. Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol. 2007; 25(26): 4057-4065.
- 29Gilbert J, Schell MJ, Zhao X, et al. A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma. Oral Oncol. 2015; 51(4): 376-382.
- 30Chen Y, Duda DG. Targeting immunosuppression after standard sorafenib treatment to facilitate immune checkpoint blockade in hepatocellular carcinoma—an auto-commentary on clinical potential and future development. Oncoimmunology. 2015; 4(10): e1029703.
- 31Chen Y, Ramjiawan RR, Reiberger T, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015; 61(5): 1591-1602.
- 32Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013; 3(12): 1355-1363.
- 33Balan M, Mier y Teran E, Waaga-Gasser AM, et al. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem. 2015; 290(13): 8110-8120.
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