Primary bone cancers (PBC) belong to the family of mesenchymal tumors classified based on their cellular origin, extracellular matrix, genetic regulation, and epigenetic modification. The three major PBC types, Ewing sarcoma, osteosarcoma, and chondrosarcoma, are frequently aggressive tumors, highly metastatic, and typically occur in children and young adults. Despite their distinct origins and pathogenesis, these sarcoma subtypes rely upon common signaling pathways to promote tumor progression, metastasis, and survival. The IGF/PI3K/mTOR and AXL/YAP/TAZ pathways, in particular, have gained significant attention recently given their ties to oncogenesis, cell fate and differentiation, metastasis, and drug resistance. Naturally, these pathways – and their protein constituents – have caught the eye of the pharmaceutical industry, and a wide array of small molecule inhibitors and antibody drug-conjugates have emerged. Here, we review how the IGF/PI3K/mTOR and AXL/YAP/TAZ pathways promote PBC and highlight the drug candidates under clinical trial investigation.

原发性骨癌 (PBC) 属于间充质肿瘤家族，根据其细胞起源、细胞外基质、遗传调控和表观遗传修饰进行分类。三种主要的 PBC 类型，尤文肉瘤、骨肉瘤和软骨肉瘤，通常是侵袭性肿瘤，高度转移，通常发生在儿童和年轻人中。尽管它们的起源和发病机制不同，但这些肉瘤亚型依赖于共同的信号通路来促进肿瘤进展、转移和存活。特别是 IGF/PI3K/mTOR 和 AXL/YAP/TAZ 通路最近受到了极大的关注，因为它们与肿瘤发生、细胞命运和分化、转移和耐药性有关。自然地，这些途径——以及它们的蛋白质成分——已经引起了制药业的注意，并且出现了广泛的小分子抑制剂和抗体药物偶联物。在这里，我们回顾了 IGF/PI3K/mTOR 和 AXL/YAP/TAZ 通路如何促进 PBC 并突出临床试验研究中的候选药物。