Identification of new therapeutic target in GIST focusing on KIT transcriptional activity.

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K15329
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Juntendo University
• Principal Investigator: Ohkubo Taketo 順天堂大学, 医学部, 非常勤助教 (90732884)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: CAGE / NTRK / GIST / pfetin / KIT

Outline of Final Research Achievements

Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type gastrointestinal stromal tumors (GIST). We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases. All of these cases showed only trkB expression. Small intestinal GISTs with trkB expression showed adverse clinical outcomes compared with those without. Cap analysis of gene expression (CAGE) analysis showed that increased number of genes whose promoters were activated in trkB positive GISTs. The genetic analysis did not show amplification of NTRK2. Furthermore, imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in trkB positive GISTs. TrkB expression was found in and restricted to duodenal GISTs and more than half of small intestinal GISTs, and probably contributing to acquire aggressive phenotype in this subset.

Free Research Field

骨軟部腫瘍病理

Academic Significance and Societal Importance of the Research Achievements

十二指腸由来のGISTの全例および小腸由来のGISTの半数以上にpan-trk(trkB)タンパク質の過剰発現を認め、統計学的有意差を生じるまでには至らなかったが、trkB陽性の小腸GISTは陰性GISTと比べて予後不良となる傾向が示された。また、CAGE解析の結果からは、KCTD12とNTRK2の遺伝子発現の観点から３つに分類される可能性が示唆された。本研究からは予後不良とされる十二指腸由来のGISTの悪性度獲得にpan-trk(trkB)の発現が関与している可能性が示唆され、過剰発現を来しているtrkBタンパク質を標的とした新規治療法の可能性が示唆された。