(P 344) TRANSCRIPTOMIC ANALYSIS OF DESMOID TUMOR RESPONSE TO NIROGACESTAT: NOVEL MECHANISMS OF RESISTANCE?

Objective: The objective of this study is to characterize the mechanism(s) of treatment response and treatment resistance of desmoid tumor cells to the standard of care medication nirogacestat. Additionally, to our knowledge this is the first study to validate the novel desmoid tumor cell line PDM-625 as a relevant preclinical model of treatment response in desmoid tumors.

Methods: First we characterized the novel desmoid tumor cell line PDM-625 (ATCC) as responding to nirogacestat in vitro via cell viability assay. We then extracted RNA from treated cells along with untreated controls and conducted bulk RNAseq to biologically characterize response to the drug and conducted pathway analysis of the resulting transcriptional data. To further clinically translate these findings we obtained an RNA seq dataset from actual patient desmoid tumor samples and did transcriptional correlation studies before and after treatment to investigate biologic subtypes associated with treatment response.

Results: We characterized the response of PDM-625 cells to nirogacestat with an IC50 of approximately 30 uM. We conducted bulk RNA seq of treated cells and untreated controls and conducted pathway analysis on the resulting transcriptional data to identify pathways associated with response and resistance. We further correlated the transcriptomic data from our dataset to a publicly-available dataset of desmoid tumor patient samples to associate nirogacestat responses to molecular subtypes of desmoid tumors.

Conclusion: To our knowledge this is the first study investigating treatment response in PDM-625 cells, and our data provide proof of concept that these cells are a valid model of desmoid tumor biology and response to both nirogacestat as well as other clinically-relevant scenarios. Furthermore, the transcriptomic signatures identified represent promising targets for further translational inquiry to better understand responses and overcome treatment resistance. These studies therefore represent a significant methodological advancement in desmoid tumor model design and leverage this model to provide clinically translational data on nirogacestat response.