individualization of anti-kinase drugs for Asian cancers using genomic and proteomic analysis

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590639
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kobe University
• Principal Investigator: MUKOHARA Toru 神戸大学, 医学部附属病院, 特命准教授 (80435718)
• Project Period (FY): 2011 – 2013
• Keywords: 個別化治療 / 胃癌 / MET / HER2 / キナーゼ阻害薬

Research Abstract

Whereas cancers with amplified MET gene, an oncogene, are potentially good target of MET kinase inhibitors, emergence of acquired resistance is highly expected. Our current study using MET-amplified gastric cancer cell lines suggested that both increase in copy number and Y1230H mutation of MET gene could cause acquired resistance. While MET copy number decreased in the absence of MET inhibitor and cells regained sensitivity to it, Y1230H mutation was irreversible alteration. This finding suggested possibility of individualized treatment based on acquired resistance mechanism in the future. Our another study using HER2-amplified gastric cancer cell lines showed that suppression of phosphorylated S6K is important molecular event to enhance 5FU-induced apoptosis, so that 5FU/everolimus combination was suggested to be attractive treatment strategy for gastric cancer with HER2 amplification.

Research Products

• [Journal Article] Regulation of MET kinase inhibitor resistance by copy number of MET in gastric carcinoma cells (2014)
  • Author(s): Funakoshi Y, Mukohara T, Ekyalongo RC, Tomioka H, Kataoka Y, Yohei Shimono, Chayahara N, Toyoda M, Kiyota N, Fujiwara Y, Minami H
  • Journal Title: Oncol Res Volume: (In press)
  • Peer Reviewed
• [Journal Article] Excessive MET signaling causes acquired resistance to and addiction to MET inhibitors in MKN45 gastric cancer cell line (2013)
  • Author(s): Funakoshi Y, Mukohara T, Tomioka H, Ekyalongo RC, Kataoka Y, Inui Y, Kawamori Y, Toyoda M, Kiyota N, Fujiwara Y, Minami H
  • Journal Title: Investigational New Drugs Volume: 31 Pages: 1158-1168
  • Peer Reviewed
• [Journal Article] Inhibition of mTOR-S6K signal is necessary to enhance fluorouracil-induced apoptosis in HER2-amplified gastric cancer cells (2012)
  • Author(s): Tomioka H, Mukohara T, Kataoka Y, Ekyalongo RC, Funakoshi Y, Imai Y, Kiyota N, Fujiwara Y, Minami H
  • Journal Title: Int J Oncol Volume: 41 Pages: 551-558
  • Peer Reviewed
• [Journal Article] Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks (2012)
  • Author(s): Kataoka Y, Mukohara T, Tomioka H, Kiyota N, Fujiwara Y, Yashiro M, Hirakawa K, Hirai M, and Minami H
  • Journal Title: Invest New Drugs Volume: 30 Pages: 1352-60
  • Peer Reviewed
• [Presentation] Reversibility of acquired resistance and"addiction"to MET inhibitors (2013)
  • Author(s): Funakoshi Y, Mukohara T, Ekyalongo RC, Tomioka H, Kataoka Y, Yohei Shimono, Chayahara N, Toyoda M, Kiyota N, Fujiwara Y, Minami H
  • Organizer: AACR-NCI-EORTC International Conference on "Molecular Targets and Cancer Therapeutics"
  • Place of Presentation: ボストン
  • Year and Date: 2013-10-20
• [Presentation] Excessive MET signaling causes acquired resistance to and addiction to MET inhibitors in MKN45 gastric cancer cell line (2012)
  • Author(s): Funakoshi Y, Mukohara T, Tomioka H, Ekyalongo RC, Kataoka Y, Inui Y, Kawamori Y, Kiyota N, Fujiwara Y, Minami H
  • Organizer: EORTC-NCI-AACR symposium on "Molecular Targets and Cancer Therapeutics"
  • Place of Presentation: ダブリン
  • Year and Date: 2012-11-07