Development of lung cancer treatment targeting drug tolerance by SHP2.

• Project/Area Number: 21K08179
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Okayama University
• Principal Investigator: Ichihara Eiki 岡山大学, 大学病院, 講師 (40549705)
• Co-Investigator(Kenkyū-buntansha): 久保 寿夫 岡山大学, 大学病院, 助教 (90726928)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肺癌 / 分子標的治療 / tolerance / SHP2 / RB / EGFR / ALK / ROS1 / CDK4/6 / 非小細胞肺癌

Outline of Research at the Start

肺癌は、様々な遺伝子異常に対応した分子標的薬で著明に縮小するが、一部のがん細胞（drug tolerant細胞）が残存し後に薬剤耐性となるため根治に至らない．申請者らは、チロシンホスファターゼの一種であるSHP2を阻害するとtolerant細胞を抑制できる可能性を見出しており、本研究では様々なタイプの遺伝子異常を持つ肺がんでSHP2阻害によるtolerant細胞抑制効果を確認し、SHP2の重要性を明らかにする．研究の方法として、患者腫瘍組織移植モデル（PDXモデル）を用い、1) SHP2阻害薬による腫瘍残存抑制効果の確認、2) SHP2を介したtolerant細胞残存メカニズムの解明を行う．

Outline of Final Research Achievements

The role of SHP2 in tolerance to molecularly targeted lung cancer therapies was investigated using lung cancer cell lines with ALK, ROS1 and EGFR gene abnormalities. Using cell line and subcutaneous tumour mouse models, we showed that cancer cells that remained tolerant under exposure to the respective molecular-targeted therapies were significantly inhibited by SHP2 inhibition. Furthermore, SHP2 maintains cell cycle-associated factor RB activity and induces tolerance by maintaining the cell cycle under molecularly-targeted therapy. Inhibition of SHP2 under exposure to molecularly targeted therapies strongly suppressed RB activity. Inhibition of the cell cycle-associated factor CDK4/6 inhibited tolerance as well as SHP2 inhibition.

Academic Significance and Societal Importance of the Research Achievements

本研究により肺がん分子標的治療における薬剤toleranceにおいてSHP2が重要な役割を果たすことが明らかとなった．SHP2を標的とすることで、肺がん分子標的治療においてこれまで困難とされていた根治的効果を持つ治療開発につながる可能性がある．

Research Products

• [Journal Article] CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer (2023)
  • Author(s): Hara Naofumi、Ichihara Eiki、Kano Hirohisa、Ando Chihiro、Morita Ayako、Nishi Tatsuya、Okawa Sachi、Nakasuka Takamasa、Hirabae Atsuko、Abe Masaya、Asada Noboru、Ninomiya Kiichiro、Makimoto Go、Fujii Masanori、Kubo Toshio、Ohashi Kadoaki、Hotta Katsuyuki、Tabata Masahiro、Maeda Yoshinobu、Kiura Katsuyuki
  • Journal Title: Translational Lung Cancer Research Volume: 12 Issue: 10 Pages: 2098-2112
  • DOI: 10.21037/tlcr-23-99
  • Peer Reviewed / Open Access