Targeting the IGF/PI3K/mTOR pathway and AXL/YAP1/TAZ pathways in primary bone cancer

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.