FusOn-pLM: a fusion oncoprotein-specific language model via adjusted rate masking

Fusion oncoproteins, a class of chimeric proteins arising from chromosomal translocations, are major drivers of various pediatric cancers. These proteins are intrinsically disordered and lack druggable pockets, making them highly challenging therapeutic targets for both small molecule-based and structure-based approaches. Protein language models (pLMs) have recently emerged as powerful tools for capturing physicochemical and functional protein features but have yet to be trained on fusion oncoprotein sequences. We introduce FusOn-pLM, a fine-tuned pLM trained on a newly curated, comprehensive set of fusion oncoprotein sequences, FusOn-DB. Employing a unique cosine-scheduled masked language modeling strategy, FusOn-pLM dynamically adjusts masking rates (15%–40%) to optimize feature extraction and representation quality, surpassing baseline embeddings in fusion-specific tasks, including localization, puncta formation, and disorder prediction. FusOn-pLM uniquely predicts drug-resistant mutations, providing insights for therapeutic design that anticipates resistance mechanisms. In total, FusOn-pLM provides biologically relevant representations for advancing therapeutic discovery in fusion-driven cancers.