Shinde Aparna, Kulkoyluoglu Cotul Eylem, Chen Hao, Smith Andrew, Libring Sarah, Solorio Luis, Wendt Michael K
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
Department of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA.
Mol Biomed. 2022 Jun 22;3(1):19. doi: 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.
对靶向治疗产生耐药性仍然是HER2亚型乳腺癌的一个主要临床障碍。利用HER2乳腺癌转移的同基因进展系列，我们证明转移细胞获得对共价泛ErbB抑制剂奈拉替尼耐药性的能力增强。通过对亲本细胞和转移细胞进行RNA测序分析，发现转谷氨酰胺酶2（TG2）上调。基因敲除和过表达实验证实，TG2对于获得奈拉替尼耐药性既必要又充分。从机制上讲，我们描述了一条途径，即TG2介导NF-κB信号通路的激活，导致转移细胞中IL-6上调。IL-6的这种自分泌表达通过JAK:STAT3信号通路维持TG2的高水平。通过使用JAK1/2抑制剂鲁索替尼可以中断这种药物持续存在反馈环。在未治疗条件下，鲁索替尼的体内应用对肿瘤生长没有影响，但能有效防止耐药性的产生，与奈拉替尼联合给药时可导致肿瘤消退。总体而言，我们的研究揭示了转移性乳腺癌细胞中一种使其易于获得对ErbB靶向治疗耐药性的机制。临床上，立即应用鲁索替尼可以防止耐药性的产生，并改善患者对HER2靶向治疗的反应。
