Is secondary resistance preventable in the moleculary targeted therapy

2015 Fiscal Year Final Research Report

• Project/Area Number: 26640110
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: National Cancer Center Japan
• Principal Investigator: Nishida Toshirou 国立研究開発法人国立がん研究センター, 東病院, 病院長 (40263264)
• Co-Investigator(Renkei-kenkyūsha): TAKAHASHI Tsuyoshi 大阪大学, 医学系研究科, 助教 (50452389)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 抗がん剤耐性 / 二次遺伝子変異 / KIT遺伝子 / 次世代シークエンサー / mRNAアレイ解析

Outline of Final Research Achievements

GIST T1 cell line has been incubated with various concentrations of imatinib and generated imatinib-resistant cells with and without secondary mutations. We found the results as follows; 1. Persistent cells had great changes in the transcriptosomes, whereas resistant cells showed great changes in the genetic mutations. 2. Secondary KIT mutations found in resistant cells could not be chased into and detected in parental cells. This was also confirmed using clinical materials. 3. Phylogenetic-tree analysis, in which branch lengths represent evolutionary time measured by VAF increments, indicated that all resistant cell lines had a similar break point time in generating imatinib-resistance.
These results may suggest that, in the cell lines, imatinib-resistant cells may considered to be generated from a crowd which have expression of detoxification and apoptosis-resistance genes, but not from pre-existing parental cells.

Free Research Field

消化器外科