Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition.
Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition.
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DOI：
10.1186/s13058-016-0697-1
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发表时间：
2016-04-05
期刊：
影响因子：
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通讯作者：
Bentires-Alj M
中科院分区：
文献类型：
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作者：
Leroy C;Ramos P;Cornille K;Bonenfant D;Fritsch C;Voshol H;Bentires-Alj M
PI 3 K通路在许多癌症中过度活化，包括70%的乳腺癌。目前正在临床试验中评估PI 3 K通路的泛型和亚型特异性抑制剂。然而，当作为单一药物使用时，对PI 3 K抑制剂的临床应答不如预期有效。为了预测p110α亚型选择性抑制剂BYL 719耐药的潜在分子机制，我们开发了耐药乳腺癌细胞系，使用无偏磷酸酪氨酸蛋白质组学评估了细胞信号通路的伴随变化，并使用药理学抑制剂表征了耐药机制。我们发现IGF 1 R，IRS 1/IRS 2和p85磷酸化在抗性品系中增加。免疫共沉淀实验鉴定了IGF 1 R/IRS/p85/p110β复合物，其引起AKT/mTOR/S6 K的活化并抑制BYL 719的作用。该复合物的成员的药理学抑制降低了mTOR/S6 K活化并恢复了对BYL 719的敏感性。我们的研究表明，IGF 1 R/p110β/AKT/mTOR轴在PIK 3CA突变型乳腺癌中赋予对BYL 719的抗性。这为在携带PIK 3CA突变的乳腺肿瘤患者中联合靶向p110α与IGF 1 R或p110β提供了依据。本文的在线版本（doi：10.1186/s13058-016-0697-1）包含补充材料，可供授权用户使用。
The PI3K pathway is hyperactivated in many cancers, including 70 % of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected. In order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines, assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics and characterized the mechanism of resistance using pharmacological inhibitors. We found an increase in IGF1R, IRS1/IRS2 and p85 phosphorylation in the resistant lines. Co-immunoprecipitation experiments identified an IGF1R/IRS/p85/p110β complex that causes the activation of AKT/mTOR/S6K and stifles the effects of BYL719. Pharmacological inhibition of members of this complex reduced mTOR/S6K activation and restored sensitivity to BYL719. Our study demonstrates that the IGF1R/p110β/AKT/mTOR axis confers resistance to BYL719 in PIK3CA mutant breast cancers. This provides a rationale for the combined targeting of p110α with IGF1R or p110β in patients with breast tumors harboring PIK3CA mutations. The online version of this article (doi:10.1186/s13058-016-0697-1) contains supplementary material, which is available to authorized users.