Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy and chemoresistance of osteosarcoma pose significant challenges in its treatment, highlighting the critical need for novel therapeutic approaches. Bruton's tyrosine kinase (BTK) plays a pivotal role in B‐cell development and has been linked to various cancers, including breast, lung, and oral cancers, where it contributes to tumor growth and chemoresistance. Despite its established importance in these malignancies, the impact of BTK on osteosarcoma remains unexplored. Our study delves into the expression levels of BTK in osteosarcoma tissues by data from the GEO and TCGA database, revealing a marked increase in BTK expression compared with primary osteoblasts and a potential correlation with primary site progression. Through our investigations, we identified a subset of osteosarcoma cells, named cis‐HOS, which exhibited resistance to cisplatin. These cells displayed characteristics of cancer stem cells (CSCs), demonstrated a higher angiogenesis effect, and had an increased migration ability. Notably, an upregulation of BTK was observed in these cisplatin‐resistant cells. The application of ibrutinib, a BTK inhibitor, significantly mitigated these aggressive traits. Our study demonstrates that BTK plays a crucial role in conferring chemoresistance in osteosarcoma. The upregulation of BTK in cisplatin‐resistant cells was effectively countered by ibrutinib. These findings underscore the potential of targeting BTK as an effective strategy to overcome chemoresistance in osteosarcoma treatment.

中文翻译：

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抑制 Bruton 酪氨酸激酶以抵消骨肉瘤的化疗耐药性和干细胞样特性


骨肉瘤是一种高度侵袭性的骨癌，经常对常规化疗药物产生耐药性，导致预后和生存率不佳。骨肉瘤的恶性肿瘤和化疗耐药性对其治疗构成了重大挑战，凸显了对新型治疗方法的迫切需求。布鲁顿酪氨酸激酶 （BTK） 在 B 细胞发育中起关键作用，并与多种癌症有关，包括乳腺癌、肺癌和口腔癌，它会导致肿瘤生长和化疗耐药。尽管 BTK 在这些恶性肿瘤中的重要性已得到证实，但 BTK 对骨肉瘤的影响仍未得到探索。我们的研究通过来自 GEO 和 TCGA 数据库的数据深入研究了骨肉瘤组织中 BTK 的表达水平，揭示了与原代成骨细胞相比，BTK 表达显着增加，并且与原发部位进展存在潜在相关性。通过我们的调查，我们鉴定了一个名为 cis-HOS 的骨肉瘤细胞亚群，它表现出对顺铂的耐药性。这些细胞表现出癌症干细胞 （CSCs） 的特性，表现出更高的血管生成效应，并且具有更高的迁移能力。值得注意的是，在这些顺铂耐药细胞中观察到 BTK 的上调。BTK 抑制剂 ibrutinib 的应用显着减轻了这些侵袭性特征。我们的研究表明，BTK 在骨肉瘤中赋予化疗耐药性起着至关重要的作用。依鲁替尼有效对抗顺铂耐药细胞中 BTK 的上调。这些发现强调了靶向 BTK 作为克服骨肉瘤治疗化疗耐药性的有效策略的潜力。