赫赛汀（曲妥珠单抗）是HER2阳性乳腺癌靶向治疗的重要药物，赫赛汀耐药是成功治疗HER2阳性乳腺癌的重大挑战。既往研究发现，HER2阳性乳腺癌赫赛汀耐药细胞与敏感细胞相比，胰岛素样生长因子IGF2 → 胰岛素样生长因子受体IGF-1R → 胰岛素受体底物IRS1信号传导通路被高度激活，具体机制尚不明确。
2021年5月11日，英国《自然》旗下《自然通讯》在线发表中国广州医科大学附属肿瘤医院、广东省蛋白质修饰与降解重点实验室、美国路易斯安那州立大学医学院斯坦利·斯科特癌症中心的研究报告，探讨了HER2阳性乳腺癌 IGF2 → IGF-1R → IRS1信号传导通路被高度激活的具体机制。
该研究发现，在赫赛汀敏感细胞中，转录因子FOXO3a可调节特定的小分子核糖核酸miRNA以控制IGF2和IRS1表达，并维持IGF2 → IGF-1R → IRS1信号传导通路的基础活性。该基础活性可维持丝氨酸苏氨酸蛋白质磷酸酶2B亚基PPP3CB的表达，以限制FOXO3a磷酸化，产生针对IGF2和IRS1的miRNA。
不过，在赫赛汀耐药HER2阳性细胞中，由于磷酸化信号转导及转录激活蛋白STAT6与组蛋白脱乙酰酶HDAC1复合物对PPP3CB转录的抑制作用，故FOXO3a磷酸化水平升高，从而破坏FOXO3a与miRNA之间的负反馈抑制环，从而上调IGF2和IRS1的表达。
此外，该研究还检测到对赫赛汀治疗方案效果较差的乳腺癌患者血液IGF2和肿瘤IRS1显著增加，而HDAC1抑制剂恩替诺特（恩替司他）对赫赛汀耐药HER2阳性乳腺癌可能有效。
因此，该研究结果表明，通过破坏FOXO3a与miRNA负反馈抑制作用，可异常激活赫赛汀耐药HER2阳性乳腺癌的IGF2 → IGF-1R → IRS1信号传导，这些结果为确定预测赫赛汀耐药的生物指标和克服赫赛汀耐药的有效策略奠定了基础。
Nat Commun. 2021 May 11;12(1):2699.
Disruption of FOXO3a-miRNA feedback inhibition of IGF2/IGF-1R/IRS1 signaling confers Herceptin resistance in HER2-positive breast cancer.
Liyun Luo, Zhijie Zhang, Ni Qiu, Li Ling, Xiaoting Jia, Ying Song, Hongsheng Li, Jiansheng Li, Hui Lyu, Hao Liu, Zhimin He, Bolin Liu, Guopei Zheng.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China; Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA, USA; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou, Guangdong, China.
Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2- and IRS1-targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB, disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance.
DOI: 10.1038/s41467-021-23052-9
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