Mechanism of lenvatinib resistance in HCC-CSCs

• Project/Area Number: 20K17039
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hokkaido University
• Principal Investigator: Maehara Osamu 北海道大学, 薬学研究院, 助教 (80836338)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 癌幹細胞 / レンバチニブ / 肝細胞癌 / がん幹細胞

Outline of Research at the Start

肝細胞癌(HCC)において、lenvatinib耐性細胞の性質や,この細胞とがん幹細胞(CSCs)との関係性を検証した報告はこれまでに存在しない。そこで、本研究ではlenvatinib耐性細胞の性質やCSCsとの関係性をsorafenib耐性細胞と比較し、それぞれの耐性細胞の特異性と共通性を明らかにすることを目的として遂行される。この解明は、lenvatinib不応例を含むHCCに対する治療最適化や新規治療法開発に繋がる可能性がある。

Outline of Final Research Achievements

The following is a list of results achieved throughout the study period.
(1) Lenvatinib and sorafenib resistant cells were generated against HCC cell lines. (2)The ratio of CSCs (CD133high/CD44high) in resistant cells was different between sor- and len-resistant cells, suggesting that the nature of resistance differs between the two cell lines.(3) Although sor- and len-resistant cells had superior tumorigenic potential compared to their parent cells, there was no significant difference between the resistant cells.(4)The results of in vitro analysis of the effects of candidate genes common to resistant cells on resistance suggested that candidate genes A, B, and C may be involved in resistance in a concerted manner.

Academic Significance and Societal Importance of the Research Achievements

HCCにおいてsorafenib耐性細胞とCSCsとの関連を報告した研究は数多く存在する一方で、lenvatinib耐性細胞の性質やCSCsとの関係性を検証した報告はこれまでに報告が少なかった。さらに、それぞれの薬剤の耐性細胞同士を比較検討した報告もなかったため本研究を実施した。実際、lenvatinib耐性細胞とsorafenib耐性細胞の性質やCSCsとの関係性には特異性と共通性があることが一部ではあるが明らかになった。この解明は、lenvatinib不応例を含むHCCに対する治療最適化や新規治療法開発に繋がることが期待される。

Research Products

• [Journal Article] Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma (2023)
  • Author(s): Yang Zijian、Suda Goki、Maehara Osamu、Ohara Masatsugu、Yoda Tomoka、Sasaki Takashi、Kohya Risako、Yoshida Sonoe、Hosoda Shunichi、Tokuchi Yoshimasa、Kitagataya Takashi、Suzuki Kazuharu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Ogawa Koji、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Cancers Volume: 15 Issue: 3 Pages: 593-593
  • DOI: 10.3390/cancers15030593
  • Peer Reviewed / Open Access
• [Journal Article] Low baseline CXCL9 predicts early progressive disease in unresectable HCC with atezolizumab plus bevacizumab treatment (2022)
  • Author(s): Hosoda S、Suda G、Sho T、Ogawa K、Kimura M、Yang Z、Yoshida S、Kubo A、Tokuchi Y、Kitagataya T、Maehara O、Ohnishi S、Nakamura A、Yamada R、Ohara M、Kawagishi N、Natsuizaka M、Nakai M、Morikawa K、Furuya K、Baba M、Yamamoto Y、Suzuki K、Izumi T、Meguro T、Terashita K、Ito J、Miyagishima T、Sakamoto N
  • Journal Title: Liver Cancer Volume: - Issue: 2 Pages: 156-170
  • DOI: 10.1159/000527759
  • Peer Reviewed / Open Access
• [Journal Article] Changes in Serum Growth Factors during Lenvatinib Predict the Post Progressive Survival in Patients with Unresectable Hepatocellular Carcinoma (2022)
  • Author(s): Yang Zijian、Suda Goki、et al.,
  • Journal Title: Cancers Volume: 14 Issue: 1 Pages: 232-232
  • DOI: 10.3390/cancers14010232
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI (2021)
  • Author(s): Kubo Akinori、Suda Goki、Kimura Megumi、Maehara Osamu、Tokuchi Yoshimasa、Kitagataya Takashi、Ohara Masatsugu、Yamada Ren、Shigesawa Taku、Suzuki Kazuharu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3633-3633
  • DOI: 10.3390/cancers13143633
  • Peer Reviewed / Open Access
• [Journal Article] FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma (2021)
  • Author(s): Maehara Osamu、Suda Goki、Natsuizaka Mitsuteru、Shigesawa Taku、Kanbe Gouki、Kimura Megumi、Sugiyama Masaya、Mizokami Masashi、Nakai Masato、Sho Takuya、Morikawa Kenichi、Ogawa Koji、Ohashi Shinya、Kagawa Shingo、Kinugasa Hideaki、Naganuma Seiji、Okubo Naoto、Ohnishi Shunsuke、Takeda Hiroshi、Sakamoto Naoya
  • Journal Title: Cancer Biology & Therapy Volume: 22 Issue: 5-6 Pages: 372-380
  • DOI: 10.1080/15384047.2021.1939638
  • Peer Reviewed
• [Journal Article] Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma (2021)
  • Author(s): Shigesawa T, Suda G, Kimura M, Maehara O, Tokuchi Y, Kubo A, Yamada R, Furuya K, Baba M, Kitagataya T, Suzuki K, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: PLoS One Volume: 16(3) Issue: 3 Pages: e0247728-e0247728
  • DOI: 10.1371/journal.pone.0247728
  • Peer Reviewed / Open Access
• [Journal Article] Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling (2020)
  • Author(s): Shigesawa Taku、Morikawa Kenichi et al.
  • Journal Title: Carcinogenesis Volume: 42 Issue: 1 Pages: 58-69
  • DOI: 10.1093/carcin/bgaa049
  • Peer Reviewed / Open Access
• [Presentation] Sequential changes in growth factors during Lenvatinib treatment in patients with unresectable hepatocellular carcinoma (2021)
  • Author(s): Yang Z, Suda G, Maehara O, Ogawa K, Kubo A, Toshida S, Tokuchi Y, Kimura M, Kitagataya T, Sho T, Shigesawa T, Yamada R, Nakai M, Morikawa K, Sakamoto N.
  • Organizer: 第2回 International Liver Conference
  • Int'l Joint Research
• [Presentation] Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling (2020)
  • Author(s): 前原経、夏井坂光輝、大西俊介、坂本直哉
  • Organizer: 第79回日本癌学会学術総会