Regulation of volume-regulated anion channels alters sensitivity to platinum chemotherapy
Cisplatin-based chemotherapy is used across many common tumor types, but resistance reduces the likelihood of long-term survival. We previously found the puromycin-sensitive aminopeptidase, NPEPPS, as a druggable driver of cisplatin resistance in vitro and in vivo and in patient-derived organoids. Here, we present a general mechanism where NPEPPS interacts with the volume-regulated anion channels (VRACs) to control cisplatin import into cells and thus regulate cisplatin response across a range of cancer types. We also find the NPEPPS/VRAC gene expression ratio is a predictive measure of cisplatin response in multiple cancer cohorts, showing the broad applicability of this mechanism. Our work describes a specific mechanism of cisplatin resistance, which, given the characteristics of NPEPPS as a drug target, has the potential to improve cancer patient outcomes. In addition, we describe an intracellular mechanism regulating VRAC activity, which is critical for volume regulation in normal cells - a finding with functional implications beyond cancer.
Authors
- Sarah J. Parker (ORCID: https://orcid.org/0000-0001-8911-3615)
- Charlene B. Tilton (ORCID: https://orcid.org/0009-0004-3238-8051)
- Cailin Deiter (ORCID: https://orcid.org/0000-0002-0772-6387)
- Eric T. Clambey (ORCID: https://orcid.org/0000-0002-7972-9544)
- Saswat Mohapatra (ORCID: https://orcid.org/0000-0002-7430-7289)
- Dan Theodorescu (ORCID: https://orcid.org/0000-0002-8708-8206)
- Robert T. Jones (ORCID: https://orcid.org/0000-0001-8007-4023)
- Tahlita C.M. Zuiverloon
- Carlos Enrique Toro Gutiérrez (ORCID: https://orcid.org/0000-0002-6084-7049)
- James C. Costello (ORCID: https://orcid.org/0000-0003-3158-9682)
- Lily Elizabeth Feldman (ORCID: https://orcid.org/0000-0001-5561-7786)
- Travis P. Broneske (ORCID: https://orcid.org/0009-0003-1971-7730)
- Mathijs Scholtes (ORCID: https://orcid.org/0000-0002-5205-097X)
- Molishree Joshi (ORCID: https://orcid.org/0000-0003-4109-5918)
- Huihui Ye (ORCID: https://orcid.org/0000-0002-8307-9492)
- Michael V. Orman (ORCID: https://orcid.org/0000-0003-2681-0063)
- Tokameh Mahmoudi (ORCID: https://orcid.org/0000-0002-2060-9353)
- F.H. Qu (ORCID: https://orcid.org/0009-0008-0358-7659)
Institutions
- Cedars-Sinai Medical Center (US)
- Erasmus MC (NL)
- University of Colorado Cancer Center (US)
- Cedars-Sinai Smidt Heart Institute (US)
- Erasmus MC Cancer Institute (NL)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-13
- DOI
- https://doi.org/10.1126/sciadv.adr9364
- Citations
- 6
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.70
Funders
- Cedars-Sinai Medical Center