LAUSR

Nephroblastomas or Wilms tumors are the most common pediatric renal cancer. Across all cases, the 5-year overall survival is over 90%. This is largely in part due to brute-force, chemotherapy regimens such as dactinomycin (actD) that have been routinely used to treat Wilms tumors. However, those that do respond to treatment still face a 15% chance of relapse. Patients with anaplastic tumor histology require more toxic therapies, and yet they still face a worse prognosis of only 66% 4-year survival and relapse rate of 43%. Furthermore, recurrence cuts survival rate down to 50%. With the widespread use of actD in Wilms tumors and other childhood malignancies, understanding the mechanism to recalcitrance against this chemotherapy can potentially reveal important vulnerabilities that can be exploited in the clinic. While transcriptomic and genomic analyses have been done in Wilms tumors, no targetable pathways have been identified in actD chemotherapy-resistant and anaplastic tumor cases. To that end, we performed ribosome sequencing of actD-treated anaplastic Wilms tumor cell line WiT49 and uncovered that the proteasome pathway is preferentially translated. Moreover, loss of proteasome subunits in a CRISPR library dropout screen sensitized the cells to actD. Consistent with these findings we found upregulation of proteasome subunit levels and proteasome enzymatic activity in Wilms tumor lines following actD treatment. To interrogate the effect of cotreating bortezomib with dactinomycin in vivo, we subcutaneously implanted anaplastic Wilms tumor patient-derived xenograft (PDX) lines in NOD/SCID Gamma (NSG) mice. Combinatorial treatment was found to be retard tumor growth compared to vehicle and single drug conditions. With further investigation, our findings can provide a foundation for exploring proteasome inhibitors with dactinomycin in clinical trials. Our study has important implications to improving the outcomes for not just for recurrent and anaplastic Wilms tumors, but to other pediatric cancers that use actD as well. Citation Format: Patricia Denise Ballesteros Tiburcio, Kenneth S. Chen. Targeting the proteasome pathway in dactinomycin resistant Wilms tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2689.