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Abstract

Osteosarcoma (OS) is the most common form of primary malignant bone cancer, predominantly affecting children and young adults. Despite extensive research at the genomic and transcriptomic levels, advances in the treatment of OS have been limited, and patients with treatment-resistant OS continue to face particularly poor overall survival rates. This thesis presents a comprehensive multiomics analysis aimed at identifying the targetable proteomic landscape of treatment-resistant OS. Through unbiased mass spectrometry-based proteomic profiling, I identified three distinct subtypes of treatment-resistant OS, each associated with varying survival outcomes. Notably, in one subtype associated with poor overall survival, upregulation of MYC signalling and MYC activity emerged as prominent features. Subsequent in vitro experiments targeting this subtype through inhibition of MYC kinases CDK2 and CDK5 demonstrated potential therapeutic benefits. Overall, this work provides a detailed multi-omics characterization of treatment-resistant OS, offering insights into novel therapeutic options that may improve patient outcomes.