Targeting HER2 signaling pathway for radiosensitization Alternative strategy for therapeutic resistance
Targeting HER2 signaling pathway for radiosensitization Alternative strategy for therapeutic resistance
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DOI：
10.4161/cbt.8.24.10131
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发表时间：
2009-12-15
影响因子：
3.6
通讯作者：
Kim, In Ah
中科院分区：
文献类型：
--
作者：
No, Mina;Choi, Eun Jung;Kim, In Ah
一些研究表明，靶向HER-2信号传导以增强电离辐射的抗肿瘤活性的潜在价值。然而，包括下游途径激活在内的若干因素导致的治疗抗性是治疗的主要障碍。我们研究了靶向HER-2信号下游的抑制剂是否会对HER-2过度扩增的SKBR 3乳腺癌细胞产生放射增敏作用。使用药物抑制剂（PD 98059、UO 126）选择性抑制MEK-ERK信号并不增加SKBR 3细胞的放射增敏作用。使用药理学抑制剂（LY 294002，AKT抑制剂VIII，雷帕霉素）选择性抑制PI 3 K-AKT-mTOR途径分别显著减弱了p-AKT和p-70 S6 K的表达，并使SKBR 3细胞放射增敏。不过表达HER-2的MCF-7细胞与SKBR 3细胞相比，通过抑制该途径表现出较低的放射增敏性。用这些抑制剂预处理也引起电离辐射后典型的G（2）阻滞的显著消除，并诱导γ H2 AX灶的显著延长，表明DNA损伤修复受损。作为1类PI 3 K和mTOR的双重抑制剂，P1103有效地放射增敏SKBR 3细胞，并显示出γ H2 AX灶的显著延长。PI 3 K-AKT信号传导的抑制分别与DNA-PKs的下调相关。LY 294002或AKT抑制剂VIII预处理的细胞以凋亡为主，而雷帕霉素或P1103预处理的细胞则表现出包括自噬在内的混合性死亡模式，提示了HER-2促生存信号通路可能的抗辐射机制，为克服HER-2抑制剂联合辐射的耐药性提供了一种新的策略。
Several studies have indicated the potential value of targeting HER-2 signaling to enhance the anti-tumor activity of ionizing radiation. however, therapeutic resistance resulting from several factors, including activation of the downstream pathway, represents a major obstacle to treatment. here, we investigated whether inhibitors targeting downstream of HER-2 signaling would radiosensitize SKBR3 breast cancer cells that exhibit overamplification of HER2.Selective inhibition of MEK-ERK signaling using pharmacologic inhibitors (PD98059, UO126) did not increase the radiosensitivity of SKBR3 cells. selective inhibition of the PI3K-AKT-mTOR pathway using pharmacologic inhibitors (LY294002, AKT inhibitor VIII, Rapamycin) significantly attenuated expression of p-AKT and p-70S6K, respectively and radiosensitized SKBR3 cells. MCF-7 cells those did not overexpress HER-2, showed less radiosensitization compared to SKBR3 cells by inhibition of this pathway. Pre-treatment with these inhibitors also caused significant abrogation of typical G(2) arrest following ionizing radiation and induced marked prolongation of gamma H2AX foci indicating impairment of DNA damage repair. A dual inhibitor of Class 1 PI3K and mTOR, P1103 effectively radiosensitized SKBR3 cells and showed significant prolongation of gamma H2AX foci. Inhibition of PI3K-AKT signaling was associated with downregulation of DNA-PKs, respectively. While apoptosis was the major mode of cell death when the cells were pretreated with LY294002 or AKT inhibitor VIII, the cells were pretreated by rapamycin or P1103 showed mixed mode of cell death including autophagy.Our results suggest possible mechanisms to counteract the HER-2 prosurvival signaling implicated in radioresistance, and offer an alternative strategy to overcome resistance to HER-2 inhibitors combined with radiation.