拉帕蒂尼
曲妥珠单抗
个人识别码1
癌症研究
生物
MAPK/ERK通路
乳腺癌
信号转导
激酶
癌症
蛋白激酶A
彪马
细胞凋亡
磷酸化
细胞生物学
丝氨酸
生物化学
遗传学
作者
Susan E. Moody,Anna C. Schinzel,Shambhavi Singh,Francesca Izzo,Matthew R. Strickland,Leo Y. Luo,Sapana R. Thomas,Jesse S. Boehm,So Young Kim,Zhigang C. Wang,William C. Hahn
出处
期刊:Oncogene
[Springer Nature]
日期:2014-06-09
卷期号:34 (16): 2061-2071
被引量:85
摘要
Targeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, the BCl-2-associated death promoter, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.
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