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An anticancer strategy of genes driven by KRAS-activating mutations

Research Project

Project/Area Number 18K07957
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionShizuoka Cancer Center Research Institute

Principal Investigator

Ohnami Shumpei  静岡県立静岡がんセンター(研究所), その他部局等, 主任研究員 (60291142)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsKRAS / BMP4 / PHLDA1 / Colon cancer / Colorectal cancer / KRAS G12 mutation / Therapeutic targets / colon cancer / whole exsome sequencing / Whole exome sequencing / Gene expression profile
Outline of Final Research Achievements

In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n=390) and those carrying KRAS mutations in codon 12 (n=240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis.
At least 11 promising candidate molecules showed greater than two-fold change between the KRAS G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted P value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with KRAS G12 mutants, BMP4, PHLDA1, and GJB5 showed significantly higher expression level in KRAS G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with KRAS G12-driven CRC.

Academic Significance and Societal Importance of the Research Achievements

大腸癌では軽度異型粘膜の段階からKRASドライバー変異が認められる。従って、RAS経路はKRAS変異型大腸癌に対して魅力的な分子標的であるが、大腸癌に対するKRASシグナル伝達経路を標的とする明確な臨床治療薬は未だ存在しない。もし、大腸癌の約半数を占めるKRAS変異を阻害する分子標的薬が開発されれば、その恩恵を受ける患者さんは膨大な数に上る。報告者は遺伝的背景の異なる癌患者の新鮮凍結組織を用いた解析から、「KRAS変異によって制御されている遺伝子が癌形質獲得や悪性度の高い癌の鍵を握っている」という信念で、真の創薬ターゲットを同定し、革新的な治療薬開発の基盤を構築し、国際誌に発表した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (4 results)

All 2021 2020 2019 2018

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (2 results)

  • [Journal Article] BMP4 and PHLDA1 are plausible drug-targetable candidate genes for KRAS G12A-, G12D-, and G12V-driven colorectal cancer2021

    • Author(s)
      Ohnami S, Maruyama K, et. al.
    • Journal Title

      Molecular and Cellular Biochemistry

      Volume: 476 Issue: 9 Pages: 3469-3482

    • DOI

      10.1007/s11010-021-04172-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients.2020

    • Author(s)
      Nagashima T, Yamaguchi K, Terashima M, et al.
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 2 Pages: 687-699

    • DOI

      10.1111/cas.14290

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] KRAS G12変異大腸がんにおける治療標的遺伝子の同定2019

    • Author(s)
      大浪俊平
    • Organizer
      日本癌学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 大腸がんにおいてKRAS G12変異により発現誘導される遺伝子の同定2018

    • Author(s)
      大浪俊平
    • Organizer
      日本癌学会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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