Cancer Therapy Targeting the HER2-PI3K Pathway: Potential Impact on the Heart.
Cancer Therapy Targeting the HER2-PI3K Pathway: Potential Impact on the Heart.
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DOI：
10.3389/fphar.2012.00113
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发表时间：
2012
影响因子：
5.6
通讯作者：
Yan X
中科院分区：
文献类型：
--
作者：
Klement GL;Goukassian D;Hlatky L;Carrozza J;Morgan JP;Yan X
HER2-PI3K通路是癌症中最易发生突变的通路之一。针对这一途径的主要激酶的几种药物已经获得美国食品和药物管理局的批准，其中许多药物正在进行临床试验，用于治疗各种癌症。然而，HER2-PI3K通路对于维持心脏的生理功能也是至关重要的，特别是在心脏应激的情况下。临床研究表明，在阿霉素与曲妥珠单抗（一种阻断HER2受体的单克隆抗体）联合治疗的患者中，纽约心脏协会III/IV类心力衰竭的发生率明显高于单独接受阿霉素治疗的患者（16%对3%）。对转基因小鼠的研究也表明，该途径的其他关键激酶，如PI3Kα、PDK1、Akt和mTOR，对于保护心脏免受缺血再灌注和主动脉狭窄引起的心功能障碍具有重要作用。然而，研究也表明抑制PI3Kγ可改善衰竭心脏的心功能。此外，转基因小鼠模型的结果并不总是与该途径的药理抑制结果一致。在这里，我们将回顾这些发现，并讨论如何在癌症和心脏生物学中解决由抑制这一重要途径引起的心脏副作用。
The HER2-PI3K pathway is the one of the most mutated pathways in cancer. Several drugs targeting the major kinases of this pathway have been approved by the Food and Drug Administration and many are being tested in clinical trials for the treatment of various cancers. However, the HER2-PI3K pathway is also pivotal for maintaining the physiological function of the heart, especially in the presence of cardiac stress. Clinical studies have shown that in patients treated with doxorubicin concurrently with Trastuzumab, a monoclonal antibody that blocks the HER2 receptor, the New York Heart Association class III/IV heart failure was significantly increased compared to those who were treated with doxorubicin alone (16 vs. 3%). Studies in transgenic mice have also shown that other key kinases of this pathway, such as PI3Kα, PDK1, Akt, and mTOR, are important for protecting the heart from ischemia-reperfusion and aortic stenosis induced cardiac dysfunction. Studies, however, have also shown that inhibition of PI3Kγ improve cardiac function of a failing heart. In addition, results from transgenic mouse models are not always consistent with the outcome of the pharmacological inhibition of this pathway. Here, we will review these findings and discuss how we can address the cardiac side-effects caused by inhibition of this important pathway in both cancer and cardiac biology.
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影响因子：
3.8
作者：
Dickerson EB;Blackburn WH;Smith MH;Kapa LB;Lyon LA;McDonald JF
通讯作者：
McDonald JF
影响因子：
4.9
作者：
Gao, Xiao-Ming;Wong, Geoffrey;Du, Xiao-Jun
通讯作者：
Du, Xiao-Jun
影响因子：
5
作者：
Ceci, M;Ross, J;Condorelli, G
通讯作者：
Condorelli, G
DOI：
10.1073/pnas.91.17.8132
发表时间：
1994-08-16
影响因子：
11.1
作者：
GUY, PM;PLATKO, JV;CARRAWAY, KL
通讯作者：
CARRAWAY, KL
影响因子：
--
作者：
Ghigo, Alessandra;Morello, Fulvio;Hirsch, Emilio
通讯作者：
Hirsch, Emilio