Authors
Chauhan, S., Jones, K., Krajbich, V. A., Smith, B., McCallister, C., Bui, T., Smith, R., Woltjer, R. L., Wangsiricharoen, S., Ramsay, D., Davare, M. A.
Abstract
TFCP2-rearranged rhabdomyosarcoma is an exceptionally rare and highly aggressive malignancy driven by TFCP2 gene fusions and associated with a dismal clinical prognosis. Because standardized treatment regimens are lacking, developing representative preclinical models is critical for identifying effective therapies. Here, we present a case of a 29-year-old male with rapidly progressive, metastatic pelvic intraosseous rhabdomyosarcoma (iRMS) harboring a FUS::TFCP2 fusion and anaplastic lymphoma kinase (ALK) overexpression. To evaluate therapeutic vulnerabilities, we established a patient-derived xenograft (PDX) model that faithfully recapitulated the histologic, immunohistochemical, and molecular hallmarks of the primary tumor. High-throughput in vitro pharmacological screening of PDX-derived cells demonstrated notable resistance to standard cytotoxic chemotherapies and revealed a paradoxical and selective sensitivity profile across ALK inhibitors. The PDX-derived cells were susceptible to crizotinib, brigatinib, and ceritinib, yet resistant to the more selective second- and third-generation inhibitors alectinib and lorlatinib. Notably, next-generation ROS1/pan-TRK inhibitors (entrectinib, repotrectinib, and taletrectinib) demonstrated superior efficacy compared to the fourth-generation ALK inhibitor NVL-655. Our findings establish a validated preclinical PDX model for FUS::TFCP2 iRMS and suggest that multi-targeted tyrosine kinase inhibition may offer a more viable therapeutic strategy than narrow-spectrum ALK targeting or conventional chemotherapy.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Aug 2026.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 8
- Comments 0