IL-6激活乳腺癌糖酵解代谢通路介导曲妥珠单抗耐药的研究

Breast cancer is one of the major cancer in women. HER2 positive breast cancer has poor prognosis, which can be partly improved by trasutuzumab treatement but still remain primary or secondary trastuzumab resistance. Recent studies demonstrated that breast cancer glycolytic metabolism abmornalities were associated with trastuzumab resistance. However, the detail mechanisms remain unelusive. Our previous study found that glycolytic pathway-related HK2 and MCT4 enzymes or transporters were upregulated in trastuzumab resistance cells. Furthermore, IL-6, which was mainly secreted by cancer associated fibroblasts in tumor microenvironment, could significantly reduce the trastuzumab treatment sensitivity and cause the high expression of HIF-1α, Glut-1 and MCT4 glycolytic pathway related proteins in HER2 positive breast cancer cells. Therefore, we hypothesize that IL-6 can activate breast cancer glycolytic pathway and lead to trastuzumab treatment resistance. In this current study, we plan to find out the clear relationship between IL-6 and trastuzumab treatment resistance, and to investigate how does IL-6 cause glycolytic pathway abnormalities and treatment resistance on the basis of above information, which can help us find out effective new targets to reverse trastuzumab resistance and provide theoretical and experimental evidence to improve the clinical efficacy in HER2 positive breast cancer.

乳腺癌是女性最常见的恶性肿瘤之一，其中HER2阳性乳腺癌预后较差，曲妥珠单抗靶向治疗虽有一定疗效，但存在原发或继发耐药。近来的研究发现乳腺癌细胞中糖酵解途径异常与曲妥珠单抗治疗的耐药有关，其具体机制尚不明了。我们的前期研究发现曲妥珠单抗耐药乳腺癌细胞系高表达HK2、MCT4等糖酵解途径的关键酶及转运体；同时，乳腺癌微环境中主要由癌相关成纤维细胞分泌的IL-6可显著降低乳腺癌细胞对曲妥珠单抗治疗的敏感性，并可使HER2 阳性乳腺癌细胞高表达HIF-1α以及糖酵解途径相关的Glut-1和MCT4等蛋白，故我们推测IL-6可激活乳腺癌的糖酵解途径，从而引起曲妥珠单抗治疗的耐药。在本研究中，我们拟明确IL-6与曲妥珠单抗治疗耐药的关系，并在此基础上探讨IL-6是如何导致乳腺癌糖酵解途径异常和治疗耐药，从而帮助发现逆转曲妥珠单抗耐药的有效新靶点，为提高HER2阳性乳腺癌的临床疗效提供理论及实验依据。

乳腺癌是女性最常见的恶性肿瘤之一，其中HER2 阳性乳腺癌预后较差，曲妥珠单抗靶向治疗虽有一定疗效，但存在原发或继发耐药。近来的研究发现乳腺癌细胞中糖酵解途径异常与曲妥珠单抗治疗的耐药有关，其具体机制尚不明了。我们的前期研究发现曲妥珠单抗治疗可抑制肿瘤细胞的糖酵解代谢，且曲妥株单抗耐药乳腺癌细胞系高表达HK2、MCT4 等糖酵解途径的关键酶及转运体；而乳腺癌微环境中主要由癌相关成纤维细胞分泌的IL-6 可促进肿瘤细胞的糖酵解代谢，并显著降低乳腺癌细胞对曲妥珠单抗治疗的敏感性。进一步对IL-6介导曲妥株单抗耐药机制的探索发现，IL-6可激活PI3K/AKT/mTOR、STAT3及NF-κB信号通路，使HER2 阳性乳腺癌细胞高表达HIF-1α 以及糖酵解途径相关的Glut-1 和MCT4等蛋白，且IL-6中和抗体或下游通路抑制剂可逆转曲妥株单抗耐药。患者组织标本检测结果提示ROCK2等基因在曲妥株单抗治疗后复发患者中高表达，或可促进HER2阳性乳腺癌进展及曲妥株单抗耐药。在本研究中，我们明确了IL-6 与曲妥珠单抗治疗耐药的关系，并在此基础上探索出IL-6 是如何导致乳腺癌糖酵解途径异常和治疗耐药，从而帮助发现逆转曲妥珠单抗耐药的有效新靶点，为提高HER2 阳性乳腺癌的临床疗效提供理论及实验依据。