Epidermal growth factor receptorAcquired resistance to cetuximab is associated with the overexpression of Ras family members and the loss of radiosensitization in head and neck cancer cells
Section snippets
Reagents
The antibodies against phospho-Akt (Ser-473), Akt, phospho-ERK1/2 (Thr202/Tyr204), ERK1/2, EGFR, actin, K-Ras and GAPDH; the control-siRNA and K-RAS-siRNA; the PI3K inhibitor LY294002; the MEK inhibitor PD98059; and the ELISA kits for TGFα and AREG have been previously described [32], [33], [34], [35], [36].
The EGFR tyrosine kinase inhibitor gefitinib was provided by Selleck Chemicals (Houston, TX, USA). Erlotinib was provided from Hoffmann-La Roche Ltd. (Basel, Switzerland), and cetuximab was
Acquired resistance to cetuximab is associated with increased proliferation and post-irradiation survival as well as the loss of cetuximab-induced radiosensitization
The effects of cetuximab on the proliferation and clonogenic activity of the HNSCC cell lines UT5 and UT5R9 (UT5 cells with acquired resistance to cetuximab after treatment with cetuximab for 9 months) and primary cetuximab-resistant SAS cells were investigated. The acquired resistance of UT5R9 cells to cetuximab was associated with increased proliferation activity, with a doubling time of 26 h compared with 45 h for the UT5 control cells (Fig. 1A). Cetuximab significantly inhibited the
Discussion
Acquired resistance to cetuximab has been reported to be associated with resistance to ionizing radiation [17] and to the EGFR-TK inhibitor gefitinib [22]. K-RAS mutations that result in the constitutive activation of K-Ras are one of the most important predictive markers for the lack of a tumor cell response to cetuximab, as shown for colorectal cancer [41], [43], [44]. In the current study, we showed that cetuximab radiosensitizes UT5 cells but not SAS cells. A similar result has been
Acknowledgments
The authors would like to thank Prof. Meier (Medical Clinic V, Research Group Molecular Oncology of Solid Tumors, Justus-Liebig-University Giessen, Germany) for providing the lonafarnib. We thank Dr. Wolfgang Eicheler, Dept. of Radiation Oncology, Technical University Dresden, for performing K-RAS sequencing. This work was supported by grants from the Deutsche Forschungsgemeinschaft [Ro527/5-1 (DFG-PAK190); SFB-773-TP B02] awarded to HPR and GRK 1302/2 (T11) awarded to MT/HPR.
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2021, Environmental Toxicology and PharmacologyCitation Excerpt :The epidermal growth factor receptor (EGFR) belongs to the erbB family which consists of four closely related receptor tyrosine kinases, erbB1 (also known as EGFR), erbB2, erbB3, and erbB4 (Bethune et al., 2010; Roskoski, 2019; Saki et al., 2013).
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2019, Biochemical and Biophysical Research CommunicationsCitation Excerpt :A recent study has tried to identify genomic profiles associated with prolonged therapeutic benefit in HNC patients and found that activated Ras signaling was associated with shorter progression free survival times [20]. While Ras/MAPK signaling has long been thought to be a potential resistance mechanism for anti-EGFR therapy, there are many postulated mechanisms of EGFR targeted therapy resistance in HNC [3,21–28]. Translational approaches to overcome anti-EGFR resistance seems to focus on three potential strategies (recently reviewed by Bertotti and Sassi [29]): 1) Combination EGFR targeting strategies; 2) Parallel pathway targeting; and 3) Downstream effector targeting (as we have shown here with STAT3 inhibition).
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2016, Oral OncologyCitation Excerpt :Therapeutic failure of EGFR inhibition may occur due to the superfluous effects of EGFR’s downstream pathways MAPK/ERK and PI3K/Akt/mTOR, which can remain active even in the presence of EGFR blockade [129]. EGFR is thought to mainly contribute to DDR-mediated radioresistance through PI3K/Akt/mTOR, which promotes NHEJ DNA repair via DNA-PKcs [129–132]. In addition, upregulation of nuclear EGFR, which can occur during the process of oncogenesis, has been implicated as a mechanism of acquired radiation resistance by affecting several genes involved in DDR, including DNA-PKcs [133].
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These authors contributed equally to this work.