Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma.
Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma.
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DOI：
10.1016/j.radonc.2010.06.010
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Wheeler DL
中科院分区：
文献类型：
--
作者：
Li C;Iida M;Dunn EF;Wheeler DL
表皮生长因子受体（EGFR）的异常表达与头颈部鳞状细胞癌（HNSCC）的发生有关。第一个主要的III期临床试验证实西妥昔单抗联合放疗具有很强的生存优势。然而，西妥昔单抗和放疗都可以促进EGFR易位到细胞核，在那里它增强了对这两种方式的抵抗。在本报告中，我们试图确定如何阻断西妥昔单抗和辐射诱导的HNSCC细胞系中EGFR向细胞核的移位。我们利用三种已建立的HNSCC细胞系，SCC 1，SCC 6和SCC 1483，并在用西妥昔单抗或放射治疗后测量EGFR的核转位。然后，我们利用达沙替尼（BMS-354825），一种有效的，口服生物可利用的抑制剂的几种酪氨酸激酶，包括Src家族激酶，以确定是否SFKs阻断可以废除西妥昔单抗和辐射诱导的核EGFR易位。西妥昔单抗和放射治疗的所有三个HNSCC系导致EGFR易位到细胞核。阻断SFKs可阻断西妥昔单抗和辐射诱导的EGFR向细胞核的转移。本报告中的数据表明，西妥昔单抗和放疗均可促进EGFR向细胞核的移位，而达沙替尼可抑制这一过程。总的来说，这些发现可能表明，达沙替尼可以限制EGFR易位到细胞核，并可能增强放疗加西妥昔单抗在HNSCC中的作用。
The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab and radiation–induced translocation of EGFR to the nucleus in HNSCC cell lines. We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src Family Kinases, to determine if SFKs blockade could abrogate cetuximab and radiation-induced nuclear EGFR translocation. Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab and radiation-induced EGFR translocation to the nucleus. The data presented in this report suggests that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.