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. H...
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| Veröffentlicht in: | Science advances 2024-12, Vol.10 (50), p.eadr9364 |
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| creator | Feldman, Lily Elizabeth R Mohapatra, Saswat Jones, Robert T Scholtes, Mathijs Tilton, Charlene B Orman, Michael V Joshi, Molishree Deiter, Cailin S Broneske, Travis P Qu, Fangyuan Gutierrez, Corazon Ye, Huihui Clambey, Eric T Parker, Sarah Mahmoudi, Tokameh Zuiverloon, Tahlita Costello, James C Theodorescu, Dan |
| description | 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. |
| doi_str_mv | 10.1126/sciadv.adr9364 |
| format | Article |
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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. 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| subjects | Aminopeptidases - genetics Aminopeptidases - metabolism Animals Antineoplastic Agents - pharmacology Cell Line, Tumor Cisplatin - pharmacology Drug Resistance, Neoplasm - genetics Gene Expression Regulation, Neoplastic - drug effects Humans Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology |
| title | Regulation of volume-regulated anion channels alters sensitivity to platinum chemotherapy |
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