Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.
Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.
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DOI：
10.1038/s42003-021-02842-3
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发表时间：
2021-11-25
影响因子：
5.9
通讯作者：
Chiosis G
中科院分区：
文献类型：
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作者：
Joshi S;Gomes ED;Wang T;Corben A;Taldone T;Gandu S;Xu C;Sharma S;Buddaseth S;Yan P;Chan LYL;Gokce A;Rajasekhar VK;Shrestha L;Panchal P;Almodovar J;Digwal CS;Rodina A;Merugu S;Pillarsetty N;Miclea V;Peter RI;Wang W;Ginsberg SD;Tang L;Mattar M;de Stanchina E;Yu KH;Lowery M;Grbovic-Huezo O;O'Reilly EM;Janjigian Y;Healey JH;Jarnagin WR;Allen PJ;Sander C;Erdjument-Bromage H;Neubert TA;Leach SD;Chiosis G
由于相互作用体网络的动态结构导致的癌细胞可塑性为治疗逃避提供了令人烦恼的出路。在这里，通过应用于胰腺癌细胞系，患者生物标本以及小鼠中细胞和患者来源的异种移植物的蛋白质连接变化的系统水平探索的化学生物学方法，我们证明了相互作用组可以重新设计脆弱性。通过操纵epichaperomes，我们可以控制和预测数千种蛋白质如何在肿瘤内实时相互作用。此外，我们本质上可以迫使肿瘤进入相互作用组超连接和最大蛋白质-蛋白质相互作用能力，在这种状态下，无法部署反弹途径，并且替代信号被抑制。因此，这种方法可以启动相互作用组以增强脆弱性并提高治疗效果，使传统上表现不佳的疗法变得非常有效。这些发现为通过药理学操纵蛋白质组范围的蛋白质-蛋白质相互作用网络来克服耐药性的范例提供了原理证明。Joshi，Gomes等人采用细胞相互作用组的化学调节方法达到超连接状态，并显示与胰腺癌细胞系对特定药物的反应增加有关，包括靶向MAPK途径和PI 3 K-mTOR途径的药物。为了实现这一点，作者通过用小分子PU-H71抑制epichaperome对相互作用组进行化学调节。
Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks. Joshi, Gomes et al. employ a chemical modulation approach of the cellular interactome to a hyperconnectivity state and show association with the increased response of pancreatic cancer cell lines to specific drugs, including those that target the MAPK-pathways and PI3K-mTOR pathway. To achieve this, the authors employ chemical modulation of the interactome via epichaperome inhibition with the small molecule PU-H71.