Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK.
Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK.
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DOI：
10.1016/j.radonc.2009.09.006
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Shields JM
中科院分区：
文献类型：
--
作者：
Sambade MJ;Camp JT;Kimple RJ;Sartor CI;Shields JM
我们最近发现，拉帕替尼，EGFR/HER 2抑制剂，放射增敏的乳腺癌细胞的基础和HER 2+亚型。本研究的目的是确定拉帕替尼介导的乳腺癌放射增敏作用的下游信号通路。在乳腺肿瘤细胞中，通过免疫印迹和克隆形成细胞存活试验评估了照射（5戈伊）、拉帕替尼、CI-1040或联合治疗后EGFR下游信号传导途径的应答。在SUM 102细胞（EGFR+基底乳腺癌细胞系）中，暴露于电离辐射引起ERK 1/2和JNK的强烈激活（可被拉帕替尼阻断），以及p38、AKT或STAT 3的弱激活/无激活。当与辐射组合时，用CI-1040直接抑制MEK 1导致存活集落的95%抑制，而用SP 600125抑制JNK没有效果。拉帕替尼介导的SUM 102细胞的放射增敏作用随着组成型活性Raf的表达而完全消除。用CI-1040处理拉帕替尼抗性SUM 185细胞恢复了放射增敏作用，当与放射组合时，存活集落减少45%。这些数据表明，拉帕替尼的放射增敏作用主要通过抑制MEK/ERK介导，直接抑制该途径可能为EGFR+或HER 2+乳腺癌提供额外的放射增敏途径。
We recently showed that lapatinib, an EGFR/HER2 inhibitor, radiosensitized breast cancer cells of the basal and HER2+ subtypes. The purpose of this study was to identify the downstream signaling pathways responsible for lapatinib-mediated radiosensitization in breast cancer. Response of EGFR downstream signaling pathways were assessed by western blot and clonogenic cell survival assays in breast tumor cells after irradiation (5 Gy), lapatinib, CI-1040, or combined treatment. In SUM102 cells, an EGFR+ basal breast cancer cell line, exposure to ionizing radiation elicited strong activation of ERK1/2 and JNK, which was blocked by lapatinib, and weak/no activation of p38, AKT or STAT3. Direct inhibition of MEK1 with CI-1040 resulted in 95% inhibition of surviving colonies when combined with radiation while inhibition of JNK with SP600125 had no effect. Lapatinib-mediated radiosensitization of SUM102 cells was completely abrogated with expression of constitutively active Raf. Treatment of lapatinib-resistant SUM185 cells with CI-1040 restored radiosensitization with 45% fewer surviving colonies when combined with radiation. These data suggest that radiosensitization by lapatinib is mediated largely through inhibition of MEK/ERK and that direct inhibition of this pathway may provide an additional avenue of radiosensitization in EGFR+ or HER2+ breast cancers.
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DOI：
10.1016/s0360-3016(02)03788-4
发表时间：
2002-11-15
影响因子：
7
作者：
Buchsbaum, DJ;Bonner, JA;Raisch, KP
通讯作者：
Raisch, KP
影响因子：
4.3
作者：
Ma, Jianxun;Ye, Lanping;Wang, Xiaopeng
通讯作者：
Wang, Xiaopeng
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK
影响因子：
11.5
作者：
Carey, Lisa A.;Dees, E. Claire;Perou, Charles M.
通讯作者：
Perou, Charles M.
DOI：
10.2217/14796694.3.1.55
发表时间：
2007-02-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Finnegan, Timothy J;Carey, Lisa A
通讯作者：
Carey, Lisa A