KF1601是BCR::ABL1和FLT3的双重抑制剂,可克服FLT3+母细胞期慢性髓系白血病的耐药

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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
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引用次数: 0

摘要

由于BCR:: abl1依赖性突变和BCR:: abl1非依赖性途径导致的Blast期慢性髓系白血病(BP-CML)耐药,给临床带来了重大挑战。先前,我们报道了约50%的BP-CML病例中FLT3通路被激活,这表明通过双重抑制BCR::ABL1和FLT3进行治疗干预的潜在途径。在这里,我们旨在评估KF1601 (BCR::ABL1和FLT3的双重抑制剂)在克服BP-CML耐药方面的疗效,同时还比较了其与ponatinib的血栓炎症反应,已知ponatinib在人类中具有严重的心血管不良事件。我们的研究结果表明,即使存在T315I突变,KF1601也能有效抑制BCR::ABL1信号通路。KF1601在K562异种移植小鼠模型中实现了完全的肿瘤消退,并在原位小鼠模型中显著延长了生存期。此外,KF1601在表达FLT3和TAZ的伊马替尼耐药K562细胞中有效抑制FLT3信号通路,通过双抑制BCR::ABL1和FLT3抑制细胞增殖。使用来自患者的耐药BP-CML细胞证实了这些发现。在使用小鼠血栓模型评估血栓炎性反应时,ponatinib诱导了严重的反应,导致颈动脉闭塞和广泛的血管壁损伤。相比之下,在用KF1601处理的小鼠中,颈动脉未闭塞,血管壁完好无损。总之,KF1601在克服耐药机制(包括BCR::ABL1T315I突变)方面表现出了良好的临床前疗效,同时也解决了与BP-CML进展相关的FLT3信号。与ponatinib等现有疗法不同,KF1601具有良好的安全性,潜在地将危及生命的不良反应风险降至最低。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3+ blast phase chronic myeloid leukemia
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.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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