OSTEOSARCOMA: THE MOLECULAR BASIS OF THERAPEUTIC RESISTANCE

Abstract

Osteosarcoma remains the most common primary malignant bone tumor and continues to be associated with poor outcomes in patients with metastatic, recurrent, or treatment-refractory disease despite decades of multimodal therapeutic advances. Therapeutic resistance has emerged as the principal biological obstacle limiting durable remission and long-term survival. This systematic review synthesizes contemporary evidence regarding the molecular mechanisms underlying resistance in osteosarcoma and evaluates emerging precision oncology approaches designed to overcome treatment failure. A comprehensive literature search of PubMed and PubMed Central was performed in accordance with PRISMA 2020 guidelines, identifying studies published between January 2000 and March 2026. Following rigorous screening and eligibility assessment, 105 studies were included in the qualitative synthesis, with particular emphasis placed on 15 landmark investigations that have shaped current understanding of osteosarcoma biology. The evidence demonstrates that chemoresistance arises through a complex interplay of genomic instability, chromosomal rearrangements, clonal evolution, dysregulated DNA repair, ATP-binding cassette transporter–mediated drug efflux, cancer stem-cell plasticity, adaptive autophagy, noncoding RNA regulatory networks, and tumour microenvironmental influences. Recent advances in genomic profiling, transcriptomics, and single-cell sequencing have revealed profound intratumoral heterogeneity and identified previously unrecognized therapeutic vulnerabilities. Collectively, these findings support a transition from empiric treatment intensification toward biomarker-driven, molecularly informed therapeutic strategies. Future progress in osteosarcoma management will depend on integrating multidimensional molecular characterization with precision-based interventions capable of circumventing the biological architecture of therapeutic resistance and improving long-term clinical outcomes.