NPEPPS Is a Druggable Driver of Platinum Resistance

Robert T. Jones, Mathijs Scholtes, Andrew Goodspeed, Maryam Akbarzadeh, Saswat Mohapatra, Lily Elizabeth Feldman, Hedvig Vekony, Annie Jean, Charlene B. Tilton, Michael V. Orman, Shahla Romal, Cailin Deiter, Tsung Wai Kan, Nathaniel Xander, Stephanie P. Araki, Molishree Joshi, Mahmood Javaid, Eric T. Clambey, Ryan Layer, Teemu D. LaajalaSarah J. Parker, Tokameh Mahmoudi*, Tahlita C.M. Zuiverloon*, Dan Theodorescu*, James C. Costello*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.

Original languageEnglish
Pages (from-to)1699-1718
Number of pages20
JournalCancer Research
Volume84
Issue number10
DOIs
Publication statusPublished - 15 May 2024

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