The Role of AXL Signaling and Mutant Isocitrate Dehydrogenase 1/2 in Conventional Chondrosarcoma

Conventional chondrosarcoma (CS), the second most common primary bone malignancy, presents a significant therapeutic challenge due to high levels of resistance to chemotherapy and radiotherapy. Current treatment is limited to surgical resection, which is often incomplete due to tumor involvement of critical structures. Recent molecular profiling studies have highlighted frequent Isocitrate Dehydrogenase 1 (IDH1) and Isocitrate Dehydrogenase 2 (IDH2) mutations, along with AXL phosphorylation and AXL-associated pathway activity, as candidate molecular features in CS. However, their functional roles may vary by subtype and require context-specific interpretation. IDH1/2 mutations are thought to contribute to CS tumorigenesis through metabolic and epigenetic mechanisms, including D-2-hydroxyglutarate (D-2-HG) accumulation, altered differentiation programs, and epigenetic dysregulation, although direct mechanistic evidence in CS remains less complete than in other IDH-mutant malignancies. Concurrently, AXL, which has been implicated in epithelial-to-mesenchymal transition (EMT), immune evasion, and therapeutic resistance, is emerging as a candidate signaling node in CS biology. Potential convergence between IDH1/2-associated metabolic or epigenetic states and AXL-associated signaling remains hypothesis-generating and requires CS-specific validation. This review synthesizes current evidence on the roles of IDH1/2 mutations and dysregulation of AXL signaling in CS, emphasizing their potential contributions to tumor aggressiveness, immune suppression, and resistance to therapy. Additionally, we explore current developments in targeted therapy exploiting IDH1/2 and AXL dysregulation.