靶向 RNA 解旋酶 DDX3X 的小分子抑制剂治疗乳腺癌骨转移。
Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment.
机构信息
Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Department of Medical Oncology, University Medical Center Utrecht Cancer Center, GA, Utrecht, the Netherlands.
出版信息
Cancer Lett. 2024 Nov 1;604:217260. doi: 10.1016/j.canlet.2024.217260. Epub 2024 Sep 19.
Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.
患有乳腺癌骨转移的患者仅有有限的姑息治疗策略，因此需要有效的药物治疗。在乳腺癌患者数据中，高水平的 RNA 解旋酶 DDX3 与总生存期和骨转移不良相关。因此，我们的目标是使用 DDX3 的小分子抑制剂 RK-33 在小鼠乳腺癌骨转移模型中靶向 DDX3。组织学确认的实时成像表明，在 RK-33 治疗组中没有骨转移，而安慰剂治疗组的小鼠则有骨转移。我们从小鼠的骨转移病变中生成了一个细胞系，发现它与一个患者来源的骨转移细胞系一样对常规化疗药物产生了耐药性，但对 RK-33 没有耐药性。最后，在乳腺癌患者转移性骨样本中观察到了不同水平的 DDX3。总的来说，这项研究表明 DDX3 是乳腺癌骨转移的一个相关临床靶点，而 RK-33 可以作为这些患者的一种安全有效的治疗方法。
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