Investigation of kinase signaling related to early drug tolerance to molecular-targeted drugs and development of therapies to overcome the tolerance

• Project/Area Number: 22K20833
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Morimoto Kenji 京都府立医科大学, 医学(系)研究科(研究院), 助教 (00768806)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 治療抵抗性 / 肺癌 / KRAS-G12C / AXL / YAP / KRAS-G12C変異 / 非小細胞肺癌 / KRASG12C変異

Outline of Research at the Start

KRAS遺伝子変異については、長らく分子標的治療薬の創薬が困難とされてきた。近年、KRAS-G12C遺伝子変異に対して、ソトラシブ（KRAS-G12C阻害薬）が創薬され、分子標的治療の道が開けた。一方でKRAS-G12C阻害薬に対する早期耐性が問題となっている。
KRAS-G12C遺伝子変異陽性肺がんについては、獲得耐性機構としていくつか報告があるものの、初期治療抵抗性に関する研究はこれまでになく、臨床開発を念頭に入れた本研究の発展が期待される。

Outline of Final Research Achievements

AXL signalling is involved in therapeutic resistance to KRAS-G12C inhibitors in AXL-high-expressing KRAS-G12C mutant lung cancer. In addition, AXL inhibitors were used to confirm their efficacy in combination with KRAS-G12C inhibitors. This study has revealed one of the molecular mechanisms involved in adaptive resistance to KRAS-G12C inhibitors. Early inhibition of AXL, which is involved in adaptive resistance, may increase the therapeutic efficacy of KRAS-G12C inhibitors and delay the time to resistance.

Academic Significance and Societal Importance of the Research Achievements

本研究により、AXL高発現の KRAS-G12C変異陽性肺がんでは、AXL阻害薬とKRAS-G12C阻害薬の初期からの併用治療が、がんの「初期治療抵抗性」を克服し、再発までの期間を大幅に伸ばせる有効な治療法であることが明らかになった。この治療法が実際の患者の治療へと発展することで、KRAS-G12C変異陽性肺がん患者の治療成績を向上させると同時に、肺がんの個別化医療」の推進に大きく貢献することが期待できる。

Research Products

• [Journal Article] AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells. (2024)
  • Author(s): Morimoto K, Yamada T, Hirai S, Katayama Y, Fukui S, Sawada R, Tachibana Y, Matsui Y, Nakamura R, Ishida M, Kawachi H, Kunimasa K, Sasaki T, Nishida M, Furuya N, Watanabe S, Shiotsu S, Nishioka N, Horinaka M, Sakai T, Uehara H, Yano S, Son BK, Tokuda S, Takayama K.
  • Journal Title: Cancer Lett Volume: 587 Pages: 216692-216692
  • DOI: 10.1016/j.canlet.2024.216692
  • Peer Reviewed / Open Access
• [Presentation] AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer (2024)
  • Author(s): Kenji Morimoto; Tadaaki Yamada; Soichi Hirai; Yuki Katayama; Kei Kunimasa; Takaaki Sasaki; Makoto Nishida; Satoshi Watanabe; Shinsuke Shiotsu; Hisanori Uehara; Koichi Takayama
  • Organizer: AACR2024
  • Int'l Joint Research
• [Presentation] AXLシグナル活性化によるKRAS-G12C阻害薬の初期治療抵抗性機構の解明と治療法開発 (2023)
  • Author(s): 森本健司, 山田忠明, 平井聡一, 片山勇輝, 國政啓, 佐々木高明, 西田真, 渡部聡, 塩津伸介, 西岡直哉, 矢野聖二, 上原久典, 徳田深作, 髙山浩一
  • Organizer: 第64回日本肺癌学会学術集会
• [Presentation] Adaptive resistance to KRAS-G12C inhibitors through AXL activation in KRAS-G12C mutant tumor cells (2023)
  • Author(s): Kenji Morimoto, Tadaaki Yamada, Soichi Hirai, Yuki Kayama, Seiji Yano, Mano Horinaka, Toshiyuki Sakai, Shinsaku Tokuda, Koichi Takayama
  • Organizer: 第82回日本癌学会学術集会
• [Funded Workshop] AACR annual meeting 2023 (2023)