A TORC2-Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers
A TORC2-Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers
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DOI：
10.1158/1535-7163.mct-15-0403
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发表时间：
2015-12-01
影响因子：
5.7
通讯作者：
Moasser, Mark M.
中科院分区：
文献类型：
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作者：
Amin, Dhara N.;Ahuja, Deepika;Moasser, Mark M.
HER3在HER2扩增的癌症中所起的必要作用超出了作为二聚化伙伴或效应底物的预期，它显示出相当程度的弹性，减轻了HER2抑制剂治疗的影响。为了更好地了解这种弹性的根源，我们对HER3下游的信号网络进行了深入的化学遗传学询问。这些肿瘤的一个独特属性是TORC2的去调控。通常维持TORC2信号的上游信号在这些肿瘤中丢失，相反，TORC2由Akt驱动。我们发现，在这些癌症中，HER3作为Akt-TORC2前馈环路的缓冲臂发挥作用，而AKT-TORC2前馈环起着自我永续模块的作用。这种网络拓扑结构改变了HER3的作用，从一个条件参与的配体驱动的上游生理信号输入，转变为同心信号吞吐量的重要组成部分，在维持内稳态方面具有很高的能力。这种信令拓扑的能力从它对其任何节点处的扰动的响应中可见一斑。因此，在HER2扩增的癌症的进化过程中，一个关键的病理生理事件是失去通常驱动TORC2信号的输入信号，在Akt依赖下重新定位它，并从根本上改变HER3的作用。这种下游网络拓扑的重新编程是HER2扩增癌症发病机制中的一个关键方面，并构成了这些癌症靶向治疗的强大障碍。(C)2015年AACR。
The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt-TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus, a critical pathophysiologic event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency, and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers. (C)2015 AACR.