Studies on the mechanisms and therapeutic approach for resistance of tyrosine kinase inhibitors in mast cell tumour

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04601
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: Nippon Veterinary and Life Science University
• Principal Investigator: BONKOBARA MAKOTO 日本獣医生命科学大学, 獣医学部, 教授 (50343611)
• Co-Investigator(Kenkyū-buntansha): 道下 正貴 日本獣医生命科学大学, 獣医学部, 准教授 (50434147) ; 佐々木 崇 札幌医科大学, 医学部, 講師 (50723897) ; 呰上 大吾 日本獣医生命科学大学, 獣医学部, 准教授 (80453934)
• Co-Investigator(Renkei-kenkyūsha): TAMURA KYOICHI 日本獣医生命科学大学, 獣医学部, 助教 (00722282)
• Research Collaborator: ARIIZUMI KIYOSHI テキサス大学, サウスウエスタンメディカルセンター・医学部, 教授 ; YASUDA AKIKO 日本獣医生命科学大学, 動物医療センター, 講師 ; SHIGIHARA KAE 日本獣医生命科学大学, 動物医療センター, 助教
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 肥満細胞腫 / 犬 / チロシンキナーゼ阻害剤 / 耐性 / KIT

Outline of Final Research Achievements

The purpose of this study was to investigate the resistance mechanisms and overcoming strategies in tyrosine kinase inhibitor-resistant mast cell tumor. Using imatinib-sensitive canine neoplastic mast cell lines carrying a KIT activating mutation, imatinib-resistant sublines were established by culturing in increasing concentrations of imatinib. From the genetic and protein analysis of the imatinib-resistant sublines, it was considered that the mechanisms including 1) reactivation of KIT by emergence of second mutation in KIT gene, 2) KIT/SFK-independent activation of ERK, 3) overexpression of KIT via prolongation of its life span, or 4) combination of these mechanisms underlay the imatinib resistance in the mast cell lines. Identification of mechanism for imatinib-resistance in individual cases could be important for development of overcoming strategies in tyrosine kinase inhibitor-resistant mast cell tumor.

Free Research Field

獣医臨床病理学