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编者按：三阴性乳腺癌对内分泌药物和抗HER2药物基本无效，对于其他药物也很容易耐药。因此，预测三阴性乳腺癌耐药，或许有助确定药物对哪些患者可能有效，以及避免耐药的策略。耐药的信号转导，存在许多通路，所谓条条小路通耐药，找到这些通路的共同枢纽，成为许多科学家上下求索的关键。 2018年3月13日，美国科学促进会《科学·信号转导》发表哈佛大学医学院、贝斯以色列女执事医疗中心、哈佛大学路德维希癌症研究中心的研究报告，通过三阴性乳腺癌细胞系分析发现细胞S期（DNA合成期）激酶相关蛋白2（SKP2）高表达可以重新激活蛋白激酶B（AKT）引起磷脂酰肌醇-3-羟激酶（PI3K）抑制剂耐药。 PI3K→AKT的激酶信号转导通路失调常见于人类癌症，尤其乳腺癌，其中PI3K催化亚基（p110）α蛋白质编码基因（PIK3CA）的扩增和体细胞突变发生率较高。PI3K和AKT的许多小分子靶向抑制剂正在接受临床评价，但是其治疗效果受到剂量相关毒性反应以及耐药的限制。既往研究已经确定PI3K抑制剂的各种耐药机制，包括AKT反馈激活、新生突变、通路相互作用。该研究发现了既往未知的PI3K通路抑制剂耐药机制，导致AKT反弹活化。 该研究利用三阴性乳腺癌细胞系亚组培养细胞和小鼠肿瘤，通过PI3K抑制剂治疗或耗尽PIK3CA表达，最终促使AKT重新激活，其依赖于泛素连接酶（E3）SKP2、胰岛素样生长因子1受体（IGF-1R）激酶、磷酸肌醇依赖性激酶-1（PDK-1）以及调节细胞生长和代谢的雷帕霉素靶蛋白复合物2（mTORC2），但是不依赖于PI3K活性或磷脂酰肌醇三磷酸（PIP3）产生。PI3K抑制剂的耐药，与SKP2表达水平增加、AKT泛素化，培养细胞增殖、小鼠异种移植肿瘤生长相关。 总之，SKP2可使PI3K通路激酶AKT泛素化而激活，且不依赖PI3K，导致PI3K抑制剂对抑制肿瘤细胞生长无效。这些结果揭示了一种泛素信号反馈机制，三阴性乳腺癌细胞通过该机制可以对PI3K抑制剂产生耐药。 因此，对于三阴性乳腺癌患者，SKP2低表达或可预测PI3K抑制剂有效、SKP2高表达或可预测PI3K抑制剂耐药、SKP2靶向联合疗法或可避免PI3K抑制剂耐药。 相关阅读 Sci Signal. 2018 Mar 13;11(521):eaao3810. Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors. Emilie Clement, Hiroyuki Inuzuka, Naoe T. Nihira, Wenyi Wei, Alex Toker. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. Skp'ing down a path of resistance Predicting how a tumor can adapt to a drug may help identify the patients most likely to respond as well as strategies to avoid resistance. Activation of the kinase PI3K drives the growth of many cancers, but resistance to targeted PI3K pathway inhibitors is common. Clement et al. analyzed triple-negative breast cancer cell lines and found that high abundance of the ubiquitin ligase Skp2 is a predictive biomarker of PI3K inhibitor resistance. Using cultured cells and in tumors in mice, they found that Skp2 ubiquitylated the PI3K pathway kinase AKT, which promoted its activation independently of PI3K, such that PI3K inhibitors were ineffective at suppressing growth. Thus, a Skp2-targeted combination therapy may prevent PI3K inhibitor resistance in some patients with this aggressive type of breast cancer. The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA 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 PIK3CA 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 PIP3 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. DOI: 10.1126/scisignal.aao3810
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