Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab.
Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab.
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DOI：
10.4161/cbt.8.8.7903
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发表时间：
2009-04
影响因子：
3.6
通讯作者：
Harari PM
中科院分区：
文献类型：
--
作者：
Wheeler DL;Iida M;Kruser TJ;Nechrebecki MM;Dunn EF;Armstrong EA;Huang S;Harari PM
表皮生长因子受体（EGFR）是一种受体酪氨酸激酶，在肿瘤发生中起主要作用。西妥昔单抗是一种EGFR阻断抗体，FDA批准用于转移性结直肠癌（mCRC）和头颈部鳞状细胞癌（HNSCC）患者。虽然西妥昔单抗对一部分癌症患者显示出很强的临床获益，但大多数患者对西妥昔单抗治疗难以治疗。我们报道了西妥昔单抗耐药NSCLC细胞系NCI-H226细胞具有继发于改变的运输/降解的EGFR的稳态表达和活性增加，并且EGFR表达和活性的这种增加导致HER3和下游存活信号的超活化。我们现在提供的数据表明，Src家族激酶（SFKs）在西妥昔单抗耐药细胞中高度活化，并增强EGFR对HER3和PI（3）K/Akt的活化。使用Src激酶抑制剂达沙替尼的研究降低了HER3和PI（3）K/Akt活性。此外，当用达沙替尼处理时，西妥昔单抗耐药细胞对西妥昔单抗重新敏感。这些结果表明，SFKs和EGFR合作获得性耐药西妥昔单抗，并提出了一个合理的临床策略，调查针对EGFR和SFKs的组合治疗西妥昔单抗获得性耐药的患者。
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.
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影响因子：
8
作者：
Fu, Y-N;Yeh, C-L;Chen, Y-R
通讯作者：
Chen, Y-R
DOI：
10.1073/pnas.92.15.6981
发表时间：
1995-07-18
影响因子：
11.1
作者：
MAA, MC;LEU, TH;PARSONS, SJ
通讯作者：
PARSONS, SJ
影响因子：
6
作者：
Zhang, Jie;Kalyankrishna, Shailaja;Kurie, Jonathan M.
通讯作者：
Kurie, Jonathan M.
影响因子：
45.3
作者：
Sequist, Lecia V.;Bell, Daphne W.;Haber, Daniel A.
通讯作者：
Haber, Daniel A.
影响因子：
4.8
作者：
Biscardi, JS;Maa, MC;Parsons, SJ
通讯作者：
Parsons, SJ