Development of innovative therapeutic strategy for MET-dependent lung cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18216
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Okayama University
• Principal Investigator: suzawa ken 岡山大学, 大学病院, 助教 (90839713)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: MET肺がん / 薬剤耐性 / 分子標的治療

Outline of Final Research Achievements

The purpose of this study was to clarify the mechanism of resistance to MET-targeted therapy in MET-aberrant lung cancer and to overcome it. Crizotinib (MET inhibitor) resistant clones of lung cancer cell lines, H1993 and EBC1, which harbor MET amplification, were established, and the following three resistance mechanisms were clarified. (1) Acquisition of resistance via loss of MET gene amplification, and acquisition of mutation and amplification of EGFR gene. For this clone, the combined therapy of crizotinib and the EGFR inhibitor, afatinib, showed significant inhibitory effect on cell growth. (2) Acquisition of resistance by increasing the expression of the SERPINE1 gene. It was confirmed that this resistance was overcome by the combined use of SERPINE1 inhibitor. (3) Acquisition of resistance by epithelial-mesenchymal transition (EMT) and activation of MEK / MAPK pathway. An inhibitory effect on cell growth was observed by the combined use of the MEK inhibitor, trametinib.

Free Research Field

呼吸器外科学

Academic Significance and Societal Importance of the Research Achievements

分子標的治療の確立には、遺伝子プロファイルに基づき、いかに治療が奏功する集団を抽出できるかが鍵となる。また分子標的薬は、治療当初は著効するが、ほぼ全例で最終的に耐性化を来すといった治療獲得耐性も重要な問題となる。MET標的療法でも数多くの耐性に関与する機序が存在することが予想さるが、現時点では未だ十分な知見は得られていない。本研究では、MET標的に対する複数の新規耐性機序が示された。この知見は肺がん治療成績の向上につながるものであり、社会的にも意義が大きいと考えられる。