American Association for Cancer Research
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Supplementary Tables from NPEPPS Is a Druggable Driver of Platinum Resistance

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posted on 2024-05-15, 07:20 authored by 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. Laajala, Sarah J. Parker, Tokameh Mahmoudi, Tahlita C.M. Zuiverloon, Dan Theodorescu, James C. Costello

Supplementary Tables 9-16

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Finnish Cancer Institute (Suomen syöpälaitos)

Anschutz Family Foundation

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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Erasmus Medisch Centrum (EMC)

History

ARTICLE 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. Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.