Integration of whole genome sequencing analysis with unique patient-derived models reveals clinically relevant drug targets in TFCP2 fusion-defined rhabdomyosarcoma.

Precision medicine is a likely future for all cancer treatment, but may have its greatest impact for less common, high-mortality and molecularly heterogeneous cancers. TFCP2-rearranged Rhabdomyosarcoma is a rare, aggressive cancer with poor survival due to a lack of effective therapies, as well as relevant models to facilitate research. Here, we establish the first matched patient-derived xenograft and cell line model for TFCP2-rearranged intraosseous Rhabdomyosarcoma (IORMS), coupled with comprehensive multi-omic and functional analysis, to discover and preclinically validate novel actionable molecular targets for this malignancy. Sequencing analyses of matched patient tumor and xenograft material revealed alterations in gene networks associated with the oncogenic, potentially targetable PI3K/AKT pathway. Preclinical assessments revealed that targeting the pathway with a small molecule PI3K/mTOR inhibitor dactolisib presents a promising treatment approach for this rare cancer, decreasing cancer cell viability in vitro and significantly reducing tumor growth in vivo. Parallel identification of the codeletion of adjacent genes CDKN2A and MTAP in these tumors, led us to further explore PRMT5 inhibition as a potential therapeutic approach. Strikingly, combined inhibition of PRMT5 and PI3K/mTOR signaling synergistically enhanced anti-tumor response and significantly improved survival in vivo. This study highlights the importance of new patient-derived models for the elucidation of the biology of rare cancers, and identification of new therapeutic entry points, with clear implications for the future treatment of TFCP2-rearranged IORMS.