209P Efficacy and safety of larotrectinib as first-line treatment for patients with TRK fusion cancer

Methods:We first established patient-derived sarcoma models that recapitulate patient tumor biology.We performed whole-genome CRISPR/Cas9 knockout screens in ex vivo myxofibrosarcoma and dedifferentiated chondrosarcoma cell models.In parallel, these models underwent customized drug-library screening using 82 clinically relevant or preclinically evaluated compounds in a sarcosphere format.Targets of interest identified from both screens were validated across 10 ex vivo sarcoma models and the underlying molecular mechanism was investigated.Patient-derived xenograft (PDX) validation is currently underway.Results: By integrating results from genetic and pharmacological screens, we identified the neddylation pathway as a selective dependency in sarcomas with HRD.Inhibition of the NEDD8-activating enzyme (NAE) with pevonedistat triggered the activation of the unfolded protein response (UPR) pathway and ultimately apoptosis specifically in cell models with HRD.This effect was accompanied by induction of CHOP and NOXA and was recapitulated by genetic disruption of the pathway.Combination screens further revealed strong drug synergy between pevonedistat and inhibitors of the DNA damage response. Conclusions:We found that sarcoma cell models with a high level of HRD were selectively sensitive to neddylation inhibition, highlighting a potential therapeutic niche for patient stratification and future clinical applications.