This study introduces a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model that exhibits acquired resistance to TRK-targeted therapy. The research highlights a novel mechanism of resistance involving an NF2 loss of function mutation, not present in the parental cell model. The resistant clones were found to be insensitive to TRK inhibition but showed increased sensitivity to MEK and mTOR inhibitors, suggesting alternative therapeutic strategies. The study also discovered drug synergy between trametinib, rapamycin, and entrectinib, and identified other small compounds that could potentially overcome resistance. This work expands the understanding of drug resistance mechanisms in sarcomas with NTRK fusions and proposes new avenues for treatment in cases of acquired resistance to TRK inhibitors. This contributes significantly to the field of functional precision oncology, offering insights that could guide future patient care.