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Published on: May 28, 2014
NPEPPS Is a Druggable Driver of Platinum Resistance
Robert T Jones1, Mathijs Scholtes2, Andrew Goodspeed1,3
1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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.
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.
Insights
Identifying puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance in bladder cancer offers a new therapeutic target. Inhibiting NPEPPS may improve patient response to platinum-based chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Platinum-based chemotherapy is a cornerstone for treating various cancers, including bladder cancer.
- Improving the efficacy of platinum drugs and extending their benefits to more patients remains a critical unmet need.
- Cisplatin response varies significantly among patients, highlighting the need to understand resistance mechanisms.
Purpose of the Study:
- To identify novel molecular drivers of cisplatin resistance in bladder cancer.
- To investigate the role of puromycin-sensitive aminopeptidase (NPEPPS) in mediating resistance to platinum-based chemotherapy.
- To evaluate NPEPPS as a potential therapeutic target for overcoming cisplatin resistance.
Main Methods:
- Multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines.
- Whole-genome CRISPR screens to identify genes driving cisplatin resistance.
- In vitro and in vivo experiments involving NPEPPS depletion or overexpression.
- Evaluation of patient-derived organoids (PDOs) for cisplatin sensitivity.
- Pharmacologic inhibition of NPEPPS.
Main Results:
- Puromycin-sensitive aminopeptidase (NPEPPS) was identified as a key driver of cisplatin resistance.
- Depletion of NPEPPS sensitized resistant bladder cancer cells to cisplatin, while its overexpression increased resistance.
- NPEPPS regulates intracellular cisplatin concentrations, affecting treatment response.
- NPEPPS inhibition or depletion increased cisplatin sensitivity in patient-derived organoids, correlating with clinical response.
Conclusions:
- NPEPPS is a druggable target that drives cisplatin resistance by modulating intracellular drug concentrations.
- Targeting NPEPPS presents a promising strategy to enhance patient response to platinum-based therapies.
- Inhibition of NPEPPS may improve outcomes and reduce toxicity in bladder cancer patients treated with cisplatin.
