Development of ferroptosis induction therapy against KRAS altered gastric cancer

• Project/Area Number: 20K16413
• 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: Kyoto University
• Principal Investigator: Kikuchi Osamu 京都大学, 医学研究科, 助教 (10869366)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 分子標的療法 / KRAS / フェロトーシス

Outline of Research at the Start

KRAS増幅胃癌は胃癌の7%を占め、変異を持たない野生型KRAS遺伝子のコピー数が増加し治療成績が不良である。このKRAS増幅胃癌細胞にMAPK経路の阻害剤を投与するとKRASの活性がむしろ上昇し、細胞内の活性酸素が増加することが知られている。本研究は、この活性酸素の増加に着目し、プログラム細胞死の一種であるフェロトーシスによる細胞死を胃癌細胞に誘導する新規薬物療法の開発を目的とする。

Outline of Final Research Achievements

We performed a genome-wide CRISPR screening and confirmatory experiments on KRAS-amplified cells, identifying multiple candidate gene knockouts that may enhance anti-tumor effects of MEK inhibitors and those that may attenuate anti-tumor effects. Among these, inhibition of GPX4 showed good anti-tumor effects in combination with MEK inhibitors. In the future, we will plan to run additional pre-clinical studies in mice and human clinical studies (phase I / II) to continue development for new treatment regimens.

Academic Significance and Societal Importance of the Research Achievements

切除不能進行胃癌の治療成績は不十分であるが、こうした難治性の胃癌の治療法開発に貢献する研究結果を得た。また今回開発している治療戦略は、胃癌の既存の標準治療で用いる薬剤とは異なるため、既存の標準治療法を使い切った胃癌症例へのさらなる生存期間延長にも貢献する可能性がある。

Research Products

• [Int'l Joint Research] Dana-Farber Cancer Institute/Broad Institute(米国)
• [Journal Article] Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study (2022)
  • Author(s): Mori Yukiko、Kikuchi Osamu、Horimatsu Takahiro、Hara Hiroki、Hironaka Shuichi、Kojima Takashi、Kato Ken、Tsushima Takahiro、Ishihara Ryu、Mukai Kumi、Uozumi Ryuji、Tada Harue、Kasai Hiroi、Kawaguchi Atsushi、Muto Manabu
  • Journal Title: Esophagus Volume: Online Issue: 3 Pages: 444-451
  • DOI: 10.1007/s10388-021-00905-2
  • Peer Reviewed
• [Presentation] Developing combination therapy with SHP2 inhibition for CIN-type gastroesophageal adenocarcinoma with KRAS amplification (2022)
  • Author(s): Osamu Kikuchi, Tianxia Li, Adam, Bass
  • Organizer: 米国AACR Annual Meeting 2022 | April 8-13, 2022（発表確定） | New Orleans
  • Int'l Joint Research