Department of Pathology, Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02215, USA.
Sci Signal. 2018 Mar 13;11(521):eaao3810. doi: 10.1126/scisignal.aao3810.
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of 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 AKT, or cross-talk pathways. 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 a PI3K inhibitor or depletion of expression ultimately promoted AKT reactivation in a manner dependent on the E3 ubiquitin ligase Skp2, the kinases IGF-1R (insulin-like growth factor 1 receptor) and PDK-1 (phosphoinositide-dependent kinase-1), and the cell growth and metabolism-regulating complex mTORC2 (mechanistic target of rapamycin complex 2), but was independent of PI3K activity or PIP production. Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice. These findings reveal a ubiquitin signaling feedback mechanism by which PI3K inhibitor resistance may emerge in aggressive breast cancer cells.
PI3K-AKT 激酶信号通路在人类癌症中经常失调，尤其是乳腺癌，其中 基因的扩增和体细胞突变在患者中高频发生。许多针对 PI3K 和 AKT 的小分子抑制剂正在进行临床评估，但剂量限制毒性和耐药性的出现限制了治疗效果。已经确定了各种对 PI3K 抑制剂的耐药机制，包括新出现的突变、AKT 的反馈激活或交叉对话途径。我们发现了一种先前未知的对 PI3K 通路抑制的耐药机制，导致 AKT 反弹激活。在一组三阴性乳腺癌细胞系中，PI3K 抑制剂的治疗或 表达的耗尽最终以依赖于 E3 泛素连接酶 Skp2、激酶 IGF-1R（胰岛素样生长因子 1 受体）和 PDK-1（磷酸肌醇依赖性激酶-1）以及细胞生长和代谢调节复合物 mTORC2（雷帕霉素复合物 2 的机制靶标）的方式促进 AKT 的重新激活，但与 PI3K 活性或 PIP 产生无关。对 PI3K 抑制剂的耐药性与 Skp2 的丰度增加、AKT 的泛素化、培养中的细胞增殖以及小鼠异种移植肿瘤的生长相关。这些发现揭示了一种泛素信号反馈机制，通过该机制，PI3K 抑制剂的耐药性可能在侵袭性乳腺癌细胞中出现。
