KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia
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 pote...
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BMC
2025-04-01
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| Online Access: | https://doi.org/10.1186/s12943-025-02292-z |
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| author | Hyun-Jin Kwon Ji Eun Shin Amir Khan So Yeon Park Jiyoung Kim Jee-Young Lee Doohyun Lee Seungyeon Lee Chun Young Im Heegyum Moon Ye Ri Han Minori Tamai Koshi Akahane Takeshi Inukai Wonhwa Lee Hyelim Kim Hong Nam Kim Sung-Min Ahn Hyun Woo Park Dong-Wook Kim |
| author_facet | Hyun-Jin Kwon Ji Eun Shin Amir Khan So Yeon Park Jiyoung Kim Jee-Young Lee Doohyun Lee Seungyeon Lee Chun Young Im Heegyum Moon Ye Ri Han Minori Tamai Koshi Akahane Takeshi Inukai Wonhwa Lee Hyelim Kim Hong Nam Kim Sung-Min Ahn Hyun Woo Park Dong-Wook Kim |
| author_sort | Hyun-Jin Kwon |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-eb24135d11bf4d5c85ea355aa5e9075a |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj-art-eb24135d11bf4d5c85ea355aa5e9075a2025-08-20T02:17:57ZengBMCMolecular Cancer1476-45982025-04-012411810.1186/s12943-025-02292-zKF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemiaHyun-Jin Kwon0Ji Eun Shin1Amir Khan2So Yeon Park3Jiyoung Kim4Jee-Young Lee5Doohyun Lee6Seungyeon Lee7Chun Young Im8Heegyum Moon9Ye Ri Han10Minori Tamai11Koshi Akahane12Takeshi Inukai13Wonhwa Lee14Hyelim Kim15Hong Nam Kim16Sung-Min Ahn17Hyun Woo Park18Dong-Wook Kim19ImmunoForge, Co. LtdDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 FOUR Program, Yonsei UniversityIcahn School of Medicine at Mount SinaiDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 FOUR Program, Yonsei UniversityImmunoForge, Co. LtdDaegu-Gyeongbuk Medical Innovation Foundation, New Drug Development CenterDaegu-Gyeongbuk Medical Innovation Foundation, New Drug Development CenterDaegu-Gyeongbuk Medical Innovation Foundation, New Drug Development CenterDaegu-Gyeongbuk Medical Innovation Foundation, New Drug Development CenterDaegu-Gyeongbuk Medical Innovation Foundation, New Drug Development CenterDepartment of Chemistry, College of Science and Technology, Duksung Women’S UniversityDepartment of Pediatrics, University of YamanashiDepartment of Pediatrics, University of YamanashiDepartment of Pediatrics, University of YamanashiDepartment of Chemistry, Sungkyunkwan UniversityBrain Science Institute, Korea, Institute of Science and Technology (KIST)Brain Science Institute, Korea, Institute of Science and Technology (KIST)ImmunoForge, Co. LtdDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 FOUR Program, Yonsei UniversityHematology Department, Eulji Medical Center, Eulji UniversityAbstract 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.https://doi.org/10.1186/s12943-025-02292-zKF1601Chronic myeloid leukemia (CML)Chronic phase CML (CP-CML)Blast phase CML (BP-CML)Tyrosine kinase inhibitor (TKI)TKI resistance |
| spellingShingle | Hyun-Jin Kwon Ji Eun Shin Amir Khan So Yeon Park Jiyoung Kim Jee-Young Lee Doohyun Lee Seungyeon Lee Chun Young Im Heegyum Moon Ye Ri Han Minori Tamai Koshi Akahane Takeshi Inukai Wonhwa Lee Hyelim Kim Hong Nam Kim Sung-Min Ahn Hyun Woo Park Dong-Wook Kim KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia Molecular Cancer KF1601 Chronic myeloid leukemia (CML) Chronic phase CML (CP-CML) Blast phase CML (BP-CML) Tyrosine kinase inhibitor (TKI) TKI resistance |
| title | KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia |
| title_full | KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia |
| title_fullStr | KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia |
| title_full_unstemmed | KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia |
| title_short | KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia |
| title_sort | kf1601 a dual inhibitor of bcr abl1 and flt3 overcomes drug resistance in flt3 blast phase chronic myeloid leukemia |
| topic | KF1601 Chronic myeloid leukemia (CML) Chronic phase CML (CP-CML) Blast phase CML (BP-CML) Tyrosine kinase inhibitor (TKI) TKI resistance |
| url | https://doi.org/10.1186/s12943-025-02292-z |
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