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

• 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
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2022: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 膵癌 / ANXA8 / MAPK阻害薬 / annexin A8 / Annexin A8 / MAPK阻害薬抵抗性

Outline of Research at the Start

難治癌である膵癌の治療成績を改善するためには有効な新規治療法の確立が求められる。私は、これまでに膵癌のMAPK阻害薬治療抵抗性に関わる分子としてAnnexin A8 (ANXA8)を同定した。本研究は、膵癌細胞株を用いてANXA8発現の機能的意義を解明するとともに、ANXA8標的治療の動物実験モデルを確立して治療応用の可能性を探求するものである。

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.

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。

Research Products

• [Journal Article] Characterization of residual cancer by comparison of a pair of organoids established from a patient with esophageal squamous cell carcinoma before and after neoadjuvant chemotherapy (2024)
  • Author(s): Fuchino Takafumi、Kurogi Shusaku、Tsukamoto Yoshiyuki、Shibata Tomotaka、Fumoto Shoichi、Fujishima Hajime、Kinoshita Keisuke、Mizukami Kazuhiro、Kodama Masaaki、Inomata Masafumi、Murakami Kazunari、Moriyama Masatsugu、Hijiya Naoki
  • Journal Title: Human Cell Volume: 37 Issue: 2 Pages: 491-501
  • DOI: 10.1007/s13577-023-01020-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Overexpression of VSNL1 Enhances Cell Proliferation in Colorectal Carcinogenesis (2023)
  • Author(s): Aiba Takayuki、Hijiya Naoki、Akagi Tomonori、Tsukamoto Yoshiyuki、Hirashita Yuka、Kinoshita Keisuke、Uchida Tomohisa、Nakada Chisato、Kurogi Shusaku、Ueda Yoshitake、Shiroshita Hidefumi、Shiraishi Norio、Murakami Kazunari、Inomata Masafumi、Moriyama Masatsugu
  • Journal Title: Pathobiology Volume: 91 Issue: 2 Pages: 121-131
  • DOI: 10.1159/000533877
  • Peer Reviewed
• [Journal Article] Association of immune‐related expression profile with sensitivity to chemotherapy in esophageal squamous cell carcinoma (2023)
  • Author(s): Tsukamoto Yoshiyuki、Kurogi Shusaku、Fujishima Hajime、Shibata Tomotaka、Fumoto Shoichi、Nishiki Kohei、Suzuki Kosuke、Etoh Tsuyoshi、Shiraishi Norio、Fuchino Takafumi、Hirashita Yuka、Nakada Chisato、Uchida Tomohisa、Inomata Masafumi、Moriyama Masatsugu、Hijiya Naoki
  • Journal Title: Cancer Science Volume: 114 Issue: 11 Pages: 4459-4474
  • DOI: 10.1111/cas.15942
  • Peer Reviewed / Open Access
• [Journal Article] Patient-Derived Ex Vivo Cultures and Endpoint Assays with Surrogate Biomarkers in Functional Testing for Prediction of Therapeutic Response (2023)
  • Author(s): Tsukamoto Yoshiyuki、Hirashita Yuka、Shibata Tomotaka、Fumoto Shoichi、Kurogi Shusaku、Nakada Chisato、Kinoshita Keisuke、Fuchino Takafumi、Murakami Kazunari、Inomata Masafumi、Moriyama Masatsugu、Hijiya Naoki
  • Journal Title: Cancers Volume: 15 Issue: 16 Pages: 4104-4104
  • DOI: 10.3390/cancers15164104
  • Peer Reviewed / Open Access
• [Journal Article] Efficient Establishment of Bile-Derived Organoids From Patients With Biliary Cancer. (2023)
  • Author(s): Kinoshita K, Tsukamoto Y, Hirashita Y, Fuchino T, Kurogi S, Uchida T, Nakada C, Matsumoto T, Okamoto K, Motomura M, Fukuchi S, Sagami R, Nagai T, Gotoh Y, Fukuda K, Ogawa R, Mizukami K, Okimoto T, Kodama M, Murakami K, Moriyama M, Hijiya N.
  • Journal Title: Lab Invest. Volume: 103 Issue: 6 Pages: 100105-100105
  • DOI: 10.1016/j.labinv.2023.100105
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor. (2023)
  • Author(s): Amada K, Hijiya N, Ikarimoto S, Yanagihara K, Hanada T, Hidano S, Kurogi S, Tsukamoto Y, Nakada C, Kinoshita K, Hirashita Y, Uchida T, Shin T, Yada K, Hirashita T, Kobayashi T, Murakami K, Inomata M, Shirao K, Aoki M, Takekawa M, Moriyama M.
  • Journal Title: Cancer Sci. Volume: 114 Issue: 5 Pages: 2189-2202
  • DOI: 10.1111/cas.15735
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids. (2022)
  • Author(s): Tsukamoto Y, Kurogi S, Shibata T, Suzuki K, Hirashita Y, Fumoto S, Yano S, Yanagihara K, Nakada C, Mieno F, Kinoshita K, Fuchino T, Mizukami K, Ueda Y, Etoh T, Uchida T, Hanada T, Takekawa M, Daa T, Shirao K, Hironaka S, Murakami K, Inomata M, Hijiya N, Moriyama M.
  • Journal Title: Lab Invest. Volume: 102 (12) Issue: 12 Pages: 1355-1366
  • DOI: 10.1038/s41374-022-00827-2
  • Peer Reviewed / Open Access
• [Presentation] 膵癌においてANXA8はMAPK阻害薬耐性に関与する (2023)
  • Author(s): 黒木秀作、泥谷直樹、塚本善之、中田知里、猪股雅史、小林隆志、守山正胤
  • Organizer: 第82回 日本癌学会学術総会
• [Presentation] Clusterinは膵癌細胞のMAPキナーゼ不応性に関与する (2023)
  • Author(s): 泥谷直樹、塚本善之、黒木秀作、中田知里、守山正胤
  • Organizer: 第82回 日本癌学会学術総会
• [Presentation] 術前化学療法の効果が低かった食道癌1例の化学療法前・後から樹立した癌オルガノイドの解析 (2023)
  • Author(s): 塚本善之、渕野貴文、黒木秀作、柴田智隆、藤島紀、板井勇介、麓祥一、猪股雅史、村上和成、泥谷直樹
  • Organizer: 第41回 日本ヒト細胞学会学術集会
• [Presentation] シスプラチン処理後のc-Junリン酸化亢進をバイオマーカーとした食道癌術前化学療法の効果予測 (2023)
  • Author(s): 塚本善之、黒木秀作、柴田智隆、鈴木浩輔、藤島紀、麓祥一、平下有香、中田知里、泥谷直樹、守山正胤
  • Organizer: 第112回 日本病理学会総会