Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer.
Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer.
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DOI：
10.1186/s43556-022-00079-y
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发表时间：
2022-06-22
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4
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获得对靶向治疗的耐药性仍然是HER2+亚型乳腺癌的主要临床障碍。利用HER2+乳腺癌转移的等基因进展系列，我们证明转移细胞对共价泛erbb抑制剂neratinib具有更高的耐药性。RNA测序分析比较亲代细胞和转移细胞，发现转谷氨酰胺酶2 （TG2）上调。基因耗竭和过表达方法证实，TG2对于获得奈拉替尼耐药性既是必要的，也是充分的。在机制上，我们描述了tg2介导NF-κB信号激活导致转移细胞中IL-6上调的途径。这种IL-6的自分泌表达通过JAK:STAT3信号传导维持TG2水平的增强。这种药物持续性反馈回路可以通过使用JAK1/2抑制剂ruxolitinib来中断。在体内应用ruxolitinib在未治疗条件下对肿瘤生长没有影响，但有效地阻止了耐药的获得，导致与neratinib共给药后肿瘤消退。总的来说，我们的研究揭示了转移性乳腺癌细胞的一种机制，使它们容易获得对erbb靶向治疗的耐药性。临床上，立即应用ruxolitinib可以防止获得耐药并改善患者对her2靶向治疗的反应。在线版本包含补充资料，下载地址：10.1186/s43556-022-00079-y。
Acquisition of resistance to targeted therapies remains a major clinical obstacle for the HER2+ subtype of breast cancer. Using an isogeneic progression series of HER2+ breast cancer metastasis we demonstrate that metastatic cells have an increased capacity to acquire resistance to the covalent, pan-ErbB inhibitor, neratinib. RNA sequencing analyses comparing parental and metastatic cells identified upregulation of transglutaminase 2 (TG2). Genetic depletion and overexpression approaches established that TG2 is both necessary and sufficient for acquisition of neratinib resistance. Mechanistically, we describe a pathway in which TG2-mediates activation of NF-κB signaling leading to upregulation of IL-6 in metastatic cells. This autocrine expression of IL-6 functions to maintain enhanced levels of TG2 via JAK:STAT3 signaling. This drug persistence feedback loop can be interrupted through the use of the JAK1/2 inhibitor ruxolitinib. In vivo application of ruxolitinib had no effect on tumor growth under non-treated conditions, but effectively prevented acquisition of resistance, leading to tumor regression upon coadministration with neratinib. Overall, our studies reveal a mechanism in metastatic breast cancer cells that predisposes them to acquisition of resistance to ErbB-targeted therapeutics. Clinically, immediate application of ruxolitinib could prevent acquisition of resistance and improve patient responses to HER2-targeted therapies. The online version contains supplementary material available at 10.1186/s43556-022-00079-y.