Ack1介导新型EGFR三代抑制剂120067耐药机制研究

EGFR T790M突变是EGFR一代抑制剂耐药最主要的原因（>50%），有效抑制该突变的三代抑制剂是新的研究热点。120067是本课题组合作开发的具有我国自主知识产权的EGFR三代抑制剂，其活性与选择性与上市药物AZD9291相当，并在I/II期临床研究显示出了良好的安全耐受性和治疗效果。. 本课题围绕120067展开新耐药生物标志物的发现和机制研究。通过耐药与亲本细胞差异分析，发现了全新的耐药标志分子Ack1。本项目将深入研究Ack1及其上下游分子在耐药中的作用，探讨Ack1介导耐药的具体机制，确定克服耐药的有效联用策略并进行临床验证。旨在确证120067关键的新耐药生物标志物，以更好地指导其临床合理用药，推进其临床研发进程，并为同类抑制剂耐药机制研究提供参考，也为Ack1作为NSCLC治疗潜在新靶点提供思路。

The first-generation EGFR inhibitors, such as gefitinib and erlotinib, have been proved for the treatment of non-small cell lung cancer (NSCLC) containing EGFR sensitizing mutations. However, acquired resistance limits the clinical use of the first-generation EGFR inhibitors, of which EGFR T790M point mutation is the most leading cause of resistance (>50%). Therefore, the development of the third-generation EGFR inhibitors that selectively inhibit the EGFR T790M mutation while sparing EGFR WT has become a hot spot for NSCLC treatment. Compound 120067 is a novel third-generation EGFR inhibitor developed by our research group. It effectively inhibits the EGFR T790M resistant mutation and EGFR sensitizing mutations while exhibits less potency on EGFR WT, which shows activity and selectivity comparable to that of AZD9291, the only third-generation EGFR inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of EGFR T790M+ NSCLC patients. 120067 with good pharmacokinetic properties has been developed into Phase I /II clinical trial in China, and exhibits great clinical safety and effects..In our previous work, we had successfully constructed 120067 resistant H1975 cells lines and subcutaneous xenografts. By analyzing the difference between the resistant cells and the parental cells, a totally new resistance biomarker Ack1 was discovered and the preliminary mechanism studies had been performed. In this research, we are going to study on the function of Ack1 as well as its upstream and downstream molecules, explore its mechanisms mediating resistance to 120067, identify effective strategies to overcome drug resistance and carry out clinical verification. The study will not only lay the foundation for clinical strategies to overcome 120067 resistance and provide new ideas for the clinical rational drug use of other third generation EGFR inbitors, but also highlight the potential value of Ack1 in drug resistance and provide the basis for Ack1 as a novel target for antitumor therapy in NSCLC.