t-Darpp Promotes Enhanced EGFR Activation and New Drug Synergies in Her2-Positive Breast Cancer Cells.
t-Darpp Promotes Enhanced EGFR Activation and New Drug Synergies in Her2-Positive Breast Cancer Cells.
复制标题
DOI：
10.1371/journal.pone.0132267
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kane SE
中科院分区：
文献类型：
--
作者：
Denny EC;Kane SE
Trastuzumab has led to improved survival rates of HER2+ breast cancer patients. However, acquired resistance remains a problem in the majority of cases. t-Darpp is over-expressed in trastuzumab-resistant cell lines and its over-expression is sufficient for conferring the resistance phenotype. Although its mechanism of action is unknown, t-Darpp has been shown to increase cellular proliferation and inhibit apoptosis. We have reported that trastuzumab-resistant BT.HerR cells that over-express endogenous t-Darpp are sensitized to EGFR inhibition in the presence (but not the absence) of trastuzumab. The purpose of the current study was to determine if t-Darpp might modulate sensitivity to EGFR inhibitors in trastuzumab-resistant cells. Using EGFR tyrosine kinase inhibitors AG1478, gefitinib and erlotinib, we found that trastuzumab-resistant SK.HerR cells were sensitized to EGFR inhibition, compared to SK-Br-3 controls, even in the absence of trastuzumab. t-Darpp knock-down in SK.HerR cells reversed their sensitivity to EGFR inhibition. Increased EGFR sensitivity was also noted in SK.tDp cells that stably over-express t-Darpp. High levels of synergy between trastuzumab and the EGFR inhibitors were observed in all cell lines with high t-Darpp expression. These cells also demonstrated more robust activation of EGFR signaling and showed greater EGFR stability than parental cells. The T75A phosphorylation mutant of t-Darpp did not confer sensitivity to EGFR inhibition nor activation of EGFR signaling. The over-expression of t-Darpp might facilitate enhanced EGFR signaling as part of the trastuzumab resistance phenotype. This study suggests that the presence of t-Darpp in HER2+ cancers might predict the enhanced response to dual HER2/EGFR targeting.
登录
查看更多内容
影响因子：
3.7
作者：
Gu L;Waliany S;Kane SE
通讯作者：
Kane SE
影响因子：
37.3
作者：
Vangamudi, Bhavatarini;Peng, Dun-Fa;Belkhiri, Abbes
通讯作者：
Belkhiri, Abbes
影响因子：
45.3
作者：
DiGiovanna, MP;Stern, DF;Thor, AD
通讯作者：
Thor, AD
影响因子：
11.2
作者：
Hong, Jun;Katsha, Ahmed;El-Rifai, Wael
通讯作者：
El-Rifai, Wael
影响因子：
7.3
作者：
Suo, Z;Risberg, B;Nesland, JM
通讯作者：
Nesland, JM