Identification of resistance factors and development of novel strategy to overcome resistance in treatment-resistant chronic myeloid leukemia

• Project/Area Number: 20K07145
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kindai University
• Principal Investigator: NISHIDA Shozo 近畿大学, 薬学部, 教授 (40208187)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 慢性骨髄性白血病 / BCR-ABL1阻害薬 / 治療抵抗性

Outline of Research at the Start

本研究計画では、現在、慢性骨髄性白血病の治療薬として用いられているBCR-ABL1阻害薬の耐性獲得機序とその克服法を見出すことを目指す。具体的には慢性骨髄性白血病細胞株を用いて、BCR-ABL1阻害薬耐性細胞を作製し、これを用いて遺伝子発現及び変異等の網羅的解析を行い、耐性因子の同定を行う。また、同定した因子を阻害する分子標的薬を選択し、用いることで、耐性克服の治療法の開発を行う。

Outline of Final Research Achievements

We established BCR-ABL1 inhibitor-resistant cells in human chronic myeloid leukemia cells, analyzed the mechanism of resistance acquisition, and found that activation of the bypass signaling pathway is involved. Furthermore, we found that BCR-ABL1 inhibitor resistance can be overcome by molecularly targeted drugs that inhibit this bypass pathway. These results may contribute to the clinical treatment of BCR-ABL1 inhibitor-resistant chronic myeloid leukemia when it emerges. The results of this study are summarized in the main publications section.

Academic Significance and Societal Importance of the Research Achievements

慢性骨髄性白血病の治療には、BCR-ABL1阻害薬が用いられるが、約30%の患者で耐性や生じ、治療が困難となる。この耐性の原因はBCR-ABL1の点変異と点変異以外に分類され、点変異に対しては治療薬の開発が進んでいるが、点変異以外の原因については不明な点が多いことから有効な治療法が存在しない。本成果において、慢性骨髄性白血病におけるBCR-ABL1阻害薬耐性にバイパス経路活性化によるERK1/2活性化が耐性の要因であることを見出し、この阻害により耐性が克服されることを明らかにした。これらの結果により、BCR-ABL1阻害薬耐性患者の生命予後の改善に貢献できると考えている。

Research Products

• [Journal Article] Hypoxia-inducible factor 1α inhibitor induces cell death via suppression of BCR-ABL1 and Met expression in BCR-ABL1 tyrosine kinase inhibitor sensitive and resistant chronic myeloid leukemia cells (2023)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Kimura A, Tanaka R, Nagayoshi S, Hoshida T, Tanabe K, Nishida S.
  • Journal Title: BMB Rep. Volume: 56 Issue: 2 Pages: 78-83
  • DOI: 10.5483/bmbrep.2022-0095
  • Peer Reviewed / Open Access
• [Journal Article] Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy (2023)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Kishimoto K, Takefuji H, Taniwaki Y, Ueda M, Hoshida T, Tanabe K, Nishida S.
  • Journal Title: Cancer Cell Int. Volume: 23 Issue: 1 Pages: 1-13
  • DOI: 10.1186/s12935-023-02884-z
  • Peer Reviewed / Open Access
• [Journal Article] Bim downregulation by activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance in multiple myeloma cells (2023)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Kishimoto K, Tanaka R, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Clin Exp Med. Volume: － Issue: 5 Pages: 1-11
  • DOI: 10.1007/s10238-022-00951-9
  • Peer Reviewed
• [Journal Article] Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells (2023)
  • Author(s): Tsubaki M, Takeda T, Koumoto Y, Usami T, Matsuda T, Seki S, Sakai K, Nishio K, Nishida S.
  • Journal Title: Cell Prolif. Volume: － Issue: 6 Pages: 1-9
  • DOI: 10.1111/cpr.13420
  • Peer Reviewed / Open Access
• [Journal Article] Combination treatment with statins and bezafibrate induces myotoxicity via inhibition of geranylgeranyl pyrophosphate biosynthesis and Rho activation in L6 myoblasts and myotube cells (2022)
  • Author(s): Tsubaki M, Takeda T, Mastuda T, Kimura A, Yanae M, Maeda A, Hoshida T, Tanabe K, Nishida S.
  • Journal Title: J Physiol Pharmacol. Volume: 73 Pages: 137-152
  • Peer Reviewed / Open Access
• [Journal Article] Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells (2022)
  • Author(s): Tsurushima K, Tsubaki M, Takeda T, Matsuda T, Kimura A, Takefuji H, Okada A, Sakamoto C, Ishizaka T, Nishida S.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 15 Pages: 1-13
  • DOI: 10.3390/ijms23158681
  • Peer Reviewed / Open Access
• [Journal Article] Perifosine enhances the potential antitumor effect of 5-fluorourasil and oxaliplatin in colon cancer cells harboring the PIK3CA mutation (2021)
  • Author(s): Morii Y, Tsubaki M, Takeda T, Otubo R, Seki S, Yamatomo Y, Imano M, Satou T, Shimomura K, Nishida S.
  • Journal Title: Eur J Pharmacol. Volume: 898 Pages: 173957-173957
  • DOI: 10.1016/j.ejphar.2021.173957
  • Peer Reviewed
• [Journal Article] Interleukin 19 suppresses RANKL-induced osteoclastogenesis via the inhibition of NF-κB and p38MAPK activation and c-Fos expression in RAW264.7 cells. (2021)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Yamamoto Y, Higashinaka A, Yamamoto K, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Cytokine Volume: 144 Pages: 155591-155591
  • DOI: 10.1016/j.cyto.2021.155591
  • Peer Reviewed
• [Journal Article] FTI-277 and GGTI-289 induce apoptosis via inhibition of the Ras/ERK and Ras/mTOR pathway in head and neck carcinoma HEp-2 and HSC-3 cells. (2021)
  • Author(s): Tateishi K, Tsubaki M, Takeda T, Yamatomo Y, Imano M, Satou T, Nishida S.
  • Journal Title: J BUON Volume: 26 Pages: 606-612
  • Peer Reviewed
• [Journal Article] Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells (2021)
  • Author(s): Tsubaki M, Genno S, Takeda T, Matsuda T, Kimura N, Yamashita Y, Morii Y, Shimomura K, Nishida S.
  • Journal Title: Biomedicines Volume: 9 Issue: 1 Pages: 35-35
  • DOI: 10.3390/biomedicines9010035
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells (2021)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Seki S, Tomonari Y, Koizumi S, Nagatakiya M, Katsuyama M, Yamamoto Y, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Biomedicines Volume: 9 Issue: 1 Pages: 33-33
  • DOI: 10.3390/biomedicines9010033
  • Peer Reviewed / Open Access
• [Journal Article] Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice (2021)
  • Author(s): Kato N, Tateishi K, Tsubaki M, Takeda T, Matsumoto M, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Pharmaceuticals (Basel). Volume: 14 Issue: 1 Pages: 30-30
  • DOI: 10.3390/ph14010030
  • Peer Reviewed / Open Access
• [Journal Article] The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells (2020)
  • Author(s): Tsubaki M, Seki S, Takeda T, Chihara A, Arai Y, Morii Y, Imano M, Satou T, Shimomura K, Nishida S.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 21 Pages: 7905-7905
  • DOI: 10.3390/ijms21217905
  • Peer Reviewed / Open Access
• [Presentation] SGK1/NF-NB経路活性化が多発性骨髄腫でのプロテアソーム阻害薬耐性に寄与する. (2022)
  • Author(s): 木村 智裕、椿 正寛、武田 朋也、原田 祐希、岸本 真祐子、鶴島 克将、星田 唯史、西田 升三.
  • Organizer: 第72回日本薬学会近畿支部総会・大会
• [Presentation] Perifosine enhances the sensitivity to oxaliplatin and 5-fluorourasil in PIK3CA-mutated colon cancer. (2022)
  • Author(s): Honoka Takefuji, Masanobu Tsubaki, Tomoya Takeda, Takuya Matsuda, Akihiro Kimura, Shozo Nishida.
  • Organizer: The 81th Annual Meeting of the Japanese Cancer Association
• [Presentation] HGF/Met/NF-kappaB 経路による骨芽細胞および骨髄間質細胞における RANKL 発現の制御機構. (2022)
  • Author(s): 岸本 佳奈、椿 正寛、武田 朋也、松田 拓弥、竹藤 帆花、西田 升三.
  • Organizer: 第26回日本がん分子標的治療学会学術集会
• [Presentation] AT9283 suppresses proliferation in tyrosine kinase inhibitor sensitive and resistant chronic myeloid leukemia cells by inhibition of Aurora A and Aurora B. (2022)
  • Author(s): Tomoya Takeda, Masanobu Tsubaki, Shozo Nishida.
  • Organizer: The 5rd International Cancer Research Symposium of Training Plan for Oncology Professionals
  • Int'l Joint Research
• [Presentation] Akt 阻害剤は PIK3CA 変異大腸癌においてオキサリプラチン及び 5-フルオロウラシルの感受性を増大させる (2021)
  • Author(s): 森井 悠介、椿 正寛、武田 朋也、松田 拓弥、山本 裕太、岸本 佳奈、西田 升三
  • Organizer: 第25回日本がん分子標的治療学会学術集会
• [Presentation] Akt inhibitor enhances the sensitivity to oxaliplatin and 5-fluorourasil in PIK3CA-mutated colon cancer (2021)
  • Author(s): Shozo Nishida, Masanobu Tsubaki, Tomoya Takeda, TakuyaMatsuda, Yuuta Yamamoto, Kana Kishimoto
  • Organizer: The 80th Annual Meeting of the Japanese Cancer Association
• [Presentation] Perifosine enhances sensitivity of oxaliplatin and 5-fluorourasil in PIK3CA-mutated colorectal cancer. (2020)
  • Author(s): Yuuta Yamamoto, Masanobu Tsubaki, Tomoya Takeda, Shiori Seki, Shozo Nishida.
  • Organizer: The 79th Annual Meeting of the Japanese Cancer Association
• [Presentation] Rhosin suppressed tumor metastasis by inhibition Rho/YAP pathway and expression of RHAMM and CXCR4. (2020)
  • Author(s): Shuji Genno, Masanobu Tsubaki, Tomoya Takeda, Shozo Nishida.
  • Organizer: The 79th Annual Meeting of the Japanese Cancer Association