Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells.
Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells.
复制标题
西妥昔单抗诱导的 MET 激活是结肠癌细胞中的一种新型耐药机制
DOI：
10.3390/ijms15045838
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发表时间：
2014-04-04
影响因子：
5.6
通讯作者：
Qu X
中科院分区：
文献类型：
--
作者：
Song N;Liu S;Zhang J;Liu J;Xu L;Liu Y;Qu X
异常MET表达和肝细胞生长因子（HGF）信号转导与促进靶向药物耐药性有关;然而，表皮生长因子受体（EGFR）抑制剂诱导的MET活化介导靶向治疗耐药性仍然难以捉摸。在这项研究中，我们发现西妥昔单抗诱导的MET活化有助于Caco-2结肠癌细胞对西妥昔单抗的耐药性。MET抑制或敲低使Caco-2细胞对西妥昔单抗介导的生长抑制敏感。此外，SRC活化通过与MET相互作用促进西妥昔单抗耐药。用SRC抑制剂预处理可消除西妥昔单抗介导的MET活化，并使Caco-2细胞对西妥昔单抗敏感。值得注意的是，西妥昔单抗诱导MET/SRC/EGFR复合物形成。MET抑制剂或SRC抑制剂抑制复合物中MET和SRC的磷酸化，MET抑制剂单独导致复合物形成的破坏。这些结果暗示MET或SRC的替代靶向是逆转结肠癌中西妥昔单抗耐药的合理策略。
Aberrant MET expression and hepatocyte growth factor (HGF) signaling are implicated in promoting resistance to targeted agents; however, the induced MET activation by epidermal growth factor receptor (EGFR) inhibitors mediating resistance to targeted therapy remains elusive. In this study, we identified that cetuximab-induced MET activation contributed to cetuximab resistance in Caco-2 colon cancer cells. MET inhibition or knockdown sensitized Caco-2 cells to cetuximab-mediated growth inhibition. Additionally, SRC activation promoted cetuximab resistance by interacting with MET. Pretreatment with SRC inhibitors abolished cetuximab-mediated MET activation and rendered Caco-2 cells sensitive to cetuximab. Notably, cetuximab induced MET/SRC/EGFR complex formation. MET inhibitor or SRC inhibitor suppressed phosphorylation of MET and SRC in the complex, and MET inhibitor singly led to disruption of complex formation. These results implicate alternative targeting of MET or SRC as rational strategies for reversing cetuximab resistance in colon cancer.
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影响因子：
6.4
作者：
Varkaris, Andreas;Gaur, Sanchaika;Parikh, Nila U.;Song, Jian H.;Dayyani, Farshid;Jin, Jung-Kang;Logothetis, Christopher J.;Gallick, Gary E.
通讯作者：
Gallick, Gary E.
影响因子：
3.6
作者：
Wheeler DL;Iida M;Kruser TJ;Nechrebecki MM;Dunn EF;Armstrong EA;Huang S;Harari PM
通讯作者：
Harari PM
DOI：
10.1158/1078-0432.ccr-12-1555
发表时间：
2013-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Stabile LP;He G;Lui VW;Thomas S;Henry C;Gubish CT;Joyce S;Quesnelle KM;Siegfried JM;Grandis JR
通讯作者：
Grandis JR
DOI：
10.1158/1078-0432.ccr-10-0568
发表时间：
2011-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liska D;Chen CT;Bachleitner-Hofmann T;Christensen JG;Weiser MR
通讯作者：
Weiser MR
影响因子：
28.2
作者：
Bardelli A;Corso S;Bertotti A;Hobor S;Valtorta E;Siravegna G;Sartore-Bianchi A;Scala E;Cassingena A;Zecchin D;Apicella M;Migliardi G;Galimi F;Lauricella C;Zanon C;Perera T;Veronese S;Corti G;Amatu A;Gambacorta M;Diaz LA Jr;Sausen M;Velculescu VE;Comoglio P;Trusolino L;Di Nicolantonio F;Giordano S;Siena S
通讯作者：
Siena S