Fusion-positive rhabdomyosarcoma oncofusions share a common interactome

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by at least seven distinct oncofusions.
• The mechanism by which these diverse oncofusions lead to the same cancer remained unclear.

Purpose of the Study:

• To investigate the functional relationship between different FP-RMS oncofusions.
• To identify shared molecular vulnerabilities across FP-RMS oncofusions.

Main Methods:

• Proteomic analysis to identify a shared protein network (common interactome).
• Functional assays to assess oncogenic activity and drug sensitivity.
• Gene expression profiling to understand transcriptional programs.

Main Results:

• All seven FP-RMS oncofusions are functionally interchangeable and associate with a common interactome.
• The common interactome binds overlapping target genes and drives a similar core transcriptional program.
• Thymidylate synthase was identified as preferentially required for FP-RMS growth, and the antifolate pralatrexate suppressed FP-RMS growth across all oncofusions.

Conclusions:

• Divergent FP-RMS oncofusions converge through a shared interactome.
• This shared interactome represents a common vulnerability exploitable by targeting thymidylate synthase with antifolates like pralatrexate.