(P 35) MECHANISTIC AND TRANSCRIPTOMIC ANALYSES REVEAL MUTATION-SPECIFIC THERAPEUTIC RESPONSES IN DESMOID TUMOR CELLS TREATED WITH SORAFENIB AND NIROGACESTAT

Objective: Desmoid tumors are rare fibroblastic neoplasms characterized by mutations in the β-catenin (CTNNB1 gene), with T41A and S45F variants showing differential therapeutic responses. While nirogacestat recently received FDA approval for desmoid tumors, sorafenib remains an important treatment option. Despite the routine clinical use of these compounds, little is known about the biology which underpins response or resistance to treatment. This study aims to elucidate mutation-specific therapeutic vulnerabilities in desmoid by comparing sorafenib and nirogacestat responses in CTNNB1-mutant models through integrated mechanistic and transcriptomic analyses to advance personalized treatment strategies.

Methods: We conducted comprehensive analyses using HCM-BROD-0762-C49 (T41A mutant) and DES23 (S45F mutant) desmoid cell lines in response to sorafenib and nirogacestat. Viability assays were performed at 24-48 hours with varying concentrations of both drugs. RNA sequencing was conducted to evaluate transcriptomic changes, followed by differential expression and gene set enrichment analysis. Immunofluorescence microscopy assessed β-catenin and Notch1 localization patterns following treatment.

Results: BROD-0762-C49 (T41A) exhibited increased sensitivity to both sorafenib and nirogacestat relative to DES23 (S45F) cells, consistent with established mutation-specific therapeutic responses. RNA sequencing revealed distinct transcriptomic signatures for each treatment: nirogacestat primarily affected Notch pathway genes (HES1, HEY1) with significant β-catenin downregulation (6.26-fold inhibition), while sorafenib showed effects on PDGFR/c-Abl signaling pathways. Immunofluorescence confirmed nirogacestat-mediated reduction in nuclear cleaved Notch1 levels at both timepoints, while β-catenin localization remained largely unchanged in S45F cells but showed modest reduction in T41A cells at 24 hours.

Conclusion: To our knowledge this is the first study investigating nirogacestat and sorafenib treatment response in these novel preclinical models of desmoid tumor biology. The transcriptomic signatures identified represent promising targets for further translational strategies to overcome treatment resistance, specifically NOTCH, β-catenin and KRAS signaling. Moreover, this study demonstrates mutation-specific therapeutic vulnerabilities in desmoid tumors with potential implications for personalized treatment approaches in desmoid tumor management.