Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors.
Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors.
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DOI：
10.1126/scisignal.aao3810
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发表时间：
2018-03-13
影响因子：
7.3
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Clement E;Inuzuka H;Nihira NT;Wei W;Toker A
PI3K-AKT激酶信号通路在人类癌症中经常被解除调控，特别是在乳腺癌中，PIK3CA基因的扩增和体细胞突变在患者中发生的频率很高。许多针对PI3K和AKT的小分子抑制剂正在临床评估中，但剂量限制性毒性和耐药性的出现限制了治疗效果。已经确定了多种对PI3K抑制剂的耐药机制，包括新生突变、AKT的反馈激活或串扰途径。在这里，我们发现了一种先前未知的PI3K途径抑制的抗性机制，该机制导致AKT反弹激活。在一组三阴性乳腺癌细胞系中，PI3K抑制剂治疗或PIK3CA表达缺失最终促进AKT再激活，其方式依赖于E3泛素连接酶Skp2，但不依赖于PI3K活性或PIP3生成。对PI3K抑制剂的耐药性与Skp2丰度增加、AKT泛素化、培养细胞增殖和小鼠异种移植物肿瘤生长相关。这些发现揭示了一种泛素信号反馈机制，PI3K抑制剂耐药性可能在侵袭性乳腺癌细胞中出现。
The PI3K–AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer where amplification and somatic mutations of the PIK3CA gene occur with high frequency in patients. Numerous small molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of the AKT or cross-talk pathways. Here, we found a previously unknown resistance mechanism to PI3K pathway inhibition that results in AKT rebound activation. In a subset of triple-negative breast cancer cell lines, treatment with PI3K inhibitor or depletion of PIK3CA expression ultimately promoted AKT reactivation in a manner dependent on the E3 ubiquitin ligase Skp2 but independent of PI3K activity or PIP3 production. Resistance to PI3K inhibitors correlated with increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice. The findings reveal a ubiquitin signaling feedback mechanism by which PI3K inhibitor resistance may emerge in aggressive breast cancer cells.
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影响因子：
16
作者：
Gasser JA;Inuzuka H;Lau AW;Wei W;Beroukhim R;Toker A
通讯作者：
Toker A
影响因子：
56.9
作者：
Franke, TF;Kaplan, DR;Toker, A
通讯作者：
Toker, A
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
影响因子：
4.8
作者：
Frech, M;Andjelkovic, M;Hemmings, BA
通讯作者：
Hemmings, BA
影响因子：
50.3
作者：
Elkabets M;Pazarentzos E;Juric D;Sheng Q;Pelossof RA;Brook S;Benzaken AO;Rodon J;Morse N;Yan JJ;Liu M;Das R;Chen Y;Tam A;Wang H;Liang J;Gurski JM;Kerr DA;Rosell R;Teixidó C;Huang A;Ghossein RA;Rosen N;Bivona TG;Scaltriti M;Baselga J
通讯作者：
Baselga J