Development of therapies for overcoming EMT-associated irreversible tyrosine kinase inhibitor resistance in EGFR lung cancer

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860603
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: Fukuda Koji 金沢大学, がん進展制御研究所, 特任助手 (10722548)
• Co-Investigator(Kenkyū-buntansha): Shinji Takeuchi 金沢大学, がん進展制御研究所・腫瘍内科, 助教 (90565384) ; Seiji Yano 金沢大学, がん進展制御研究所・腫瘍内科, 教授 (30294672)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: EMT / EGFR肺癌 / AXL

Outline of Final Research Achievements

Irreversible tyrosine kinase inhibitor (ITKI) for the treatment of patients with mutant EGFR NSCLC has been approved in Japan recently. However, a lot of patients could be acquired resistance after treatment. While epithelial mesenchymal transition (EMT) was reported to be associated with the resistance, no optimal therapy has been identified. In this study, we first hypothesized that AXL plays an important role in EMT resistance and examined the effect of AXL inhibition on the EMT resistant cells. However, knock-down of AXL did not change the EMT phenotypes. Interestingly, we found that knock-down of ZEB1 induced mesenchymal-epithelial transition (MET) and restored sensitivity to EGFR-TKI. Furthermore, our drug screening revealed that Drug A strongly suppressed ZEB1 expression and induced MET, as well as restored ITKI sensitivity. These results suggest that Drug A could be a novel therapeutic strategy for overcoming EMT-associated ITKI resistance in mutant EGFR lung cancer.

Free Research Field

分子腫瘍学