p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks.
p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks.
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DOI：
10.1016/j.cellsig.2014.03.013
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发表时间：
2014-08
影响因子：
4.8
通讯作者：
Weber MJ
中科院分区：
文献类型：
--
作者：
Axelrod MJ;Gordon V;Mendez RE;Leimgruber SS;Conaway MR;Sharlow ER;Jameson MJ;Gioeli DG;Weber MJ
靶向致癌驱动因子的疗法迅速诱导补偿性适应性反应，从而削弱药物有效性，导致治疗耐药性。适应性反应是稳健的细胞信号传导网络的特征，因此对共同靶向驱动因子和适应性反应的药物组合的兴趣越来越大。共同抑制致癌和适应性靶标的另一种方法是鉴定这些靶标的活性会聚的关键节点。信号传导模块之间的会聚节点代表潜在的治疗弱点，因为它们的抑制可能导致网络的崩溃，导致细胞毒性增强。在这份报告中，我们证明p70 S6激酶（p70 S6 K）可以作为一个关键节点连接HER家族和磷酸肌醇-3-激酶（PI 3 K）信号通路。我们使用高通量组合药物筛选来鉴定对靶向治疗的适应性生存反应，发现HER家族和PI 3 K代表了补偿信号通路。在单一疗法抑制两个靶点均无效的情况下，联合靶向这些途径与药物组合会产生协同细胞毒性。我们利用反相蛋白阵列并确定核糖体蛋白S6的磷酸化在HER家族和PI 3 K/哺乳动物雷帕霉素靶蛋白（mTOR）共抑制后协同下调。组成型活性p70 S6 K的表达保护细胞免于由HER家族和PI 3 K/mTOR联合抑制诱导的细胞凋亡。用表型化HER家族的小分子抑制剂直接抑制p70 S6 K和PI 3 K/mTOR共抑制。这些数据暗示p70 S6 K是HER家族/PI 3 K信号网络中的关键节点。p70 S6 K的直接抑制剂对两个上游信号传导靶标的表型共抑制的能力表明关键节点的鉴定和靶向可以克服对靶向疗法的适应性抗性。
Therapies targeting oncogenic drivers rapidly induce compensatory adaptive responses that blunt drug effectiveness, contributing to therapeutic resistance. Adaptive responses are characteristic of robust cell signaling networks, and thus there is increasing interest in drug combinations that co-target the driver and the adaptive response. An alternative approach to co-inhibiting oncogenic and adaptive targets is to identify a critical node where the activities of these targets converge. Nodes of convergence between signaling modules represent potential therapeutic vulnerabilities because their inhibition could result in collapse of the network, leading to enhanced cytotoxicity. In this report we demonstrate that p70S6 kinase (p70S6K) can function as a critical node linking HER-family and phosphoinositide-3-kinase (PI3K) pathway signaling. We used high-throughput combinatorial drug screening to identify adaptive survival responses to targeted therapies, and found that HER-family and PI3K represented compensatory signaling pathways. Co-targeting these pathways with drug combinations caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. We utilized Reverse Phase Protein Arrays and determined that phosphorylation of ribosomal protein S6 was synergistically down-regulated upon HER-family and PI3K/mammalian target of rapamycin (mTOR) co-inhibition. Expression of constitutively active p70S6K protected against apoptosis induced by combined HER-family and PI3K/mTOR inhibition. Direct inhibition of p70S6K with small molecule inhibitors phenocopied HER-family and PI3K/mTOR co-inhibition. These data implicate p70S6K as a critical node in the HER-family/PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy co-inhibition of two upstream signaling targets indicates that identification and targeting of critical nodes can overcome adaptive resistance to targeted therapies.
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DOI：
10.1158/1078-0432.ccr-10-0568
发表时间：
2011-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liska D;Chen CT;Bachleitner-Hofmann T;Christensen JG;Weiser MR
通讯作者：
Weiser MR
影响因子：
8
作者：
Basile, K. J.;Abel, E. V.;Aplin, A. E.
通讯作者：
Aplin, A. E.
影响因子：
11.5
作者：
Hennessy, Bryan T.;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
克唑替尼克服了 EGFR 突变非小细胞肺癌细胞中肝细胞生长因子介导的吉非替尼耐药性
影响因子：
2.3
作者：
Chen, Xi;Zhou, Jian-Ya;Zhou, Jian-Ying
通讯作者：
Zhou, Jian-Ying
磷脂酰肌醇3-激酶过度激活导致拉帕替尼的抗性，这是由mTOR/磷脂酰/磷脂酰肌醇3-激酶抑制剂NVP-BEZ235逆转的。
影响因子：
11.2
作者：
Eichhorn PJ;Gili M;Scaltriti M;Serra V;Guzman M;Nijkamp W;Beijersbergen RL;Valero V;Seoane J;Bernards R;Baselga J
通讯作者：
Baselga J