酪氨酸激酶SRC激活YAP-TFAP2A转录复合体促进HER2+乳腺癌对曲妥珠单抗耐药的机制研究

HER2+乳腺癌对曲妥珠单抗耐药是导致其靶向治疗失败的主要原因。临床发现激酶SRC在单抗耐药患者乳腺癌中异常激活，但SRC激活的关键底物及调控耐药应答机制并不清楚。研究显示Hippo通路效应因子YAP也参与到耐药应答中，申请人前期已证实SRC可以磷酸化YAP。近期预实验发现：1）SRC磷酸化YAP可以增强其与转录激活蛋白TFAP2A互作并促进乳腺上皮细胞增殖和肿瘤生长；2）单抗耐药乳腺癌细胞进一步增强了SRC-YAP磷酸化，而敲除YAP可以增强耐药癌细胞对曲妥珠单抗的敏感性：3）单抗耐药病人乳腺癌组织中SRC-YAP被磷酸化激活。由此推出假说：SRC激活通过增强YAP-TFAP2A互作和转录，从而促进肿瘤生长并对曲妥珠单抗耐药。本项目拟以HER2+乳腺癌细胞及临床肿瘤类器官为研究对象，深入解析SRC激活YAP-TFAP2A在单抗耐药过程中的作用机制，旨在为该类耐药癌症患者提供新的药物靶点。

The resistance of HER2 positive breast cancer to trastuzumab is the main reason for the failure of targeted therapy. Clinical studies showed the tyrosine kinase SRC was abnormally activated in HER2 positive breast tumors with trastuzumab resistance; however, the key substrate activated by SRC and the regulatory mechanism were not clear. Previous studies showed that YAP, the downstream effector of Hippo pathway, was also involved in drug resistance response. Our previous study revealed that the tyrosine kinase SRC can directly activate YAP, and our preliminary data showed that: 1) YAP phosphorylation by SRC will enhance its interaction with transcriptional factor AP2A (TFAP2A) and induce the cell proliferation and tumor growth of breast epithelial cells; 2) In HER2 positive breast cancer cells acquired with trastuzumab resistance, the tyrosine phosphorylation levels of SRC and YAP were increased, knockdown of YAP will increase the sensitivity of tumor cells to trastuzumab; 3) SRC and YAP were activated in breast cancer tissues of HER2 positive patient acquired with trastuzumab resistance. Based on these evidences, we hypothesized that tyrosine kinase SRC promoted the tumor growth and trastuzumab resistance of HER2 positive breast cancer through enhancing YAP-TFAP2A interaction and transcription. In this project, we will take use of the HER2 positive breast cancer cells with trastuzumab resistance, together with the tumor organoid model, to study the underlying mechanisms of SRC-mediated YAP-TFAP2A transcription complex activation in trastuzumab resistance of HER2 positive breast cancer. Through this study, we aim to provide new therapeutic targets for these patients with trastuzumab resistance.