Elucidation of the functional role of ANXA8 in pancreatic cancer resistance to MAPK inhibitors and its therapeutic application

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15408
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Oita University
• Principal Investigator: Kurogi Shusaku 大分大学, 医学部, 技術専門職員 (50905213)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 膵癌 / ANXA8 / MAPK阻害薬

Outline of Final Research Achievements

In previous studies, we identified ANXA8 as a molecule involved in MAPK inhibitor resistance in pancreatic cancer. In this study, we investigated the association between ANXA8 expression and clinicopathological factors in pancreatic cancer tissues and attempted to elucidate the functional significance of ANXA8. We found that ANXA8 was frequently upregulated in poorly differentiated pancreatic cancer. We also found that ANXA8 was induced by MAPK inhibitors in MAPK inhibitor-resistant pancreatic cancer cell lines and that suppression of ANXA8 enhanced the anti-proliferative effect of MAPK inhibitors. We plan to conduct further studies to identify compounds that inhibit ANXA8 expression in order to develop novel ANXA8-targeted therapies for pancreatic cancer patients.

Free Research Field

分子病理学

Academic Significance and Societal Importance of the Research Achievements

膵癌は5年生存率が10%未満と予後不良な癌である。膵癌は、約90%の症例で活性型K-ras変異によるMAPK経路の活性化が生じており、MAPK経路は重要な治療標的と考えられているが、膵癌患者を対象とした臨床試験において有効性は得られていない。本研究では、MAPK阻害薬抵抗性に関わる分子としてANXA8を見出し、ANXA8の発現を抑制するとMAPK阻害薬の抗腫瘍効果が高まることを明らかにした。すなわち、MAPK阻害薬とANXA8標的治療を併用することで、これまでにMAPK阻害薬が無効とされた膵癌症例に新たな治療戦略を提供できる可能性が期待でき、その社会的意義は極めて大きいと考えられる。