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Mol. Cancer, 14 April 2025 | https://doi.org/10.1186/s12943-025-02292-z
KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia
Hyun-Jin Kwon 1,†, Ji Eun Shin 2,†, Amir Khan 3,†, So Yeon Park 2,†, Jiyoung Kim 1, Jee-Young Lee 4, Doohyun Lee 4, Seungyeon Lee 4, Chun Young Im 4, Heegyum Moon 4, Ye Ri Han 5, Minori Tamai 6, Koshi Akahane 6,16, Takeshi Inukai 6,16, Wonhwa Lee 7, Hyelim Kim 8,12, Hong Nam Kim 8,13,14,15, Sung-Min Ahn 1,9,*, Hyun Woo Park 2,* and Dong-Wook Kim 10,11,*
1ImmunoForge, Co. Ltd, Seoul 08591, Republic of Korea.
2Department of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 FOUR Program, Yonsei University, Seoul 03722, Republic of Korea.
3Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4Daegu-Gyeongbuk Medical Innovation Foundation, New Drug Development Center, Daegu 41061, Republic of Korea.
5Department of Chemistry, College of Science and Technology, Duksung Women’S University, Seoul 01369, Republic of Korea.
6Department of Pediatrics, University of Yamanashi, Chuo, Japan.
7Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea.
8Brain Science Institute, Korea, Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
9Department of Genome Medicine and Science, College of Medicine, Gachon University, Incheon 21565, Republic of Korea.
10Hematology Department, Eulji Medical Center, Eulji University, Uijeongbu-Si, Gyeonggi-Do, Republic of Korea.
11Leukemia Omics Research Institute, Eulji University, Uijeongbu-si, Gyeonggi-Do, Republic of Korea.
12Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
13Division of Bio-Medical Science and Technology (KIST School), Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea.
14School of Mechanical Engineering, Yonsei University, Seoul 03722, Republic of Korea.
15Yonsei-KIST Convergence Research Institute, Yonsei University, Seoul 03722, Republic of Korea.
16Global Leukemia Cell-Line Assembly Network, University of Yamanashi, Kofu City, Japan.
2Department of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 FOUR Program, Yonsei University, Seoul 03722, Republic of Korea.
3Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4Daegu-Gyeongbuk Medical Innovation Foundation, New Drug Development Center, Daegu 41061, Republic of Korea.
5Department of Chemistry, College of Science and Technology, Duksung Women’S University, Seoul 01369, Republic of Korea.
6Department of Pediatrics, University of Yamanashi, Chuo, Japan.
7Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea.
8Brain Science Institute, Korea, Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
9Department of Genome Medicine and Science, College of Medicine, Gachon University, Incheon 21565, Republic of Korea.
10Hematology Department, Eulji Medical Center, Eulji University, Uijeongbu-Si, Gyeonggi-Do, Republic of Korea.
11Leukemia Omics Research Institute, Eulji University, Uijeongbu-si, Gyeonggi-Do, Republic of Korea.
12Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
13Division of Bio-Medical Science and Technology (KIST School), Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea.
14School of Mechanical Engineering, Yonsei University, Seoul 03722, Republic of Korea.
15Yonsei-KIST Convergence Research Institute, Yonsei University, Seoul 03722, Republic of Korea.
16Global Leukemia Cell-Line Assembly Network, University of Yamanashi, Kofu City, Japan.
†Hyun-Jin Kwon, Ji Eun Shin, Amir Khan and So Yeon Park contributed equally to this work.
*Corresponding authors: correspondence to Sung-Min Ahn, Hyun Woo Park or Dong-Wook Kim
Abstract
Blast phase chronic myeloid leukemia (BP-CML) poses significant clinical challenges due to its drug resistance, resulting from BCR::ABL1-dependent mutations and BCR::ABL1-independent pathways. Previously, we reported that FLT3 pathway is activated in ~ 50% of BP-CML cases, indicating a potential avenue for therapeutic intervention via dual inhibition of BCR::ABL1 and FLT3. Here, we aimed to evaluate the efficacy of KF1601, a dual inhibitor of BCR::ABL1 and FLT3, in overcoming drug resistance in BP-CML while also comparing its thrombo-inflammatory responses with those of ponatinib, known to have severe cardiovascular adverse events in human. Our findings revealed that KF1601 effectively inhibited of BCR::ABL1 signaling pathway, even in the presence of the T315I mutation. KF1601 achieved complete tumor regression in K562 xenograft mouse models, and prolonged survival significantly in orthotopic mouse models. Furthermore, KF1601 effectively inhibited the FLT3 signaling pathway in imatinib-resistant K562 cells expressing FLT3 and TAZ, suppressing cell proliferation through dual inhibition of BCR::ABL1 and FLT3. These findings were corroborated using drug-resistant BP-CML cells from patients. In assessing thrombo-inflammatory responses using a murine thrombosis model, ponatinib induced severe responses, leading to carotid artery occlusion and extensive vessel wall damage. In contrast, in mice treated with KF1601, carotid arteries remained unoccluded, with vessel walls preserved intact. In summary, KF1601 demonstrated promising preclinical efficacy in overcoming resistance mechanisms, including the BCR::ABL1T315I mutation, while also addressing FLT3 signaling implicated in BP-CML progression. Unlike existing therapies such as ponatinib, KF1601 offers a favorable safety profile, potentially minimizing the risk of life-threatening adverse effects.
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-04-15)
- 국내(교신)+국외 연구진
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