2. Academic Validation
  3. NPEPPS Is a Druggable Driver of Platinum Resistance

NPEPPS Is a Druggable Driver of Platinum Resistance

  • Cancer Res. 2024 Mar 27:OF1-OF20. doi: 10.1158/0008-5472.CAN-23-1976.
Robert T Jones # 1,  Mathijs Scholtes # 2,  Andrew Goodspeed # 1 3,  Maryam Akbarzadeh 2 4,  Saswat Mohapatra 5,  Lily Elizabeth Feldman 1,  Hedvig Vekony 1,  Annie Jean 1,  Charlene B Tilton 1,  Michael V Orman 1,  Shahla Romal 4,  Cailin Deiter 1,  Tsung Wai Kan 2 6,  Nathaniel Xander 1,  Stephanie P Araki 1,  Molishree Joshi 1 7,  Mahmood Javaid 8,  Eric T Clambey 8,  Ryan Layer 9 10,  Teemu D Laajala 1 11,  Sarah J Parker 12,  Tokameh Mahmoudi 2 4 6,  Tahlita C M Zuiverloon 2,  Dan Theodorescu 5 13 14,  James C Costello 1 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 2 Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 3 University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 4 Department of Biochemistry, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 5 Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California.
  • 6 Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
  • 7 Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 8 Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 9 Computer Science Department, University of Colorado, Boulder, Colorado.
  • 10 BioFrontiers Institute, University of Colorado, Boulder, Colorado.
  • 11 Department of Mathematics and Statistics, University of Turku, Turku, Finland.
  • 12 Smidt Heart Institute and Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
  • 13 Department of Urology, Cedars-Sinai Medical Center, Los Angeles, California.
  • 14 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
  • # Contributed equally.
PMID: 38535994 DOI: 10.1158/0008-5472.CAN-23-1976
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, whereas NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.

Significance: 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.

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