<scp>TRPM8</scp> levels determine tumor vulnerability to channel agonists
Targeted therapies have pervasively enhanced clinical protocols and significantly improved survival and quality of life of cancer patients. Mostly grounded on small molecules and antibodies targeting deregulated mechanisms in cancer cells, precision oncology approaches are limited to a few tumor types because of the paucity of clinically actionable targets. Here, we report a comparative analysis of the cation channel transient receptor potential melastatin 8 (TRPM8; also known as transient receptor potential cation channel subfamily M member 8) in lung, breast, colorectal, and prostate cancers. Our findings reveal high levels of channel expression in cores of all four carcinomas, irrespective of reduced expression of its RNA. Importantly, cancer cell lines that represent the various tumor types consistently show that sub-lethal chemotherapy dosages combined with the TRPM8 agonist D-3263 have a synergistic lethal effect. In addition, administration of D-3263 increases the cytotoxicity of 5-FU/Oxaliplatin in patient-derived colorectal cancer organoids, depending on the levels of TRPM8. Overall, our study strengthens the candidacy of TRPM8 as a molecular target for precision oncology approaches and paves the way for the design of basket trials for its clinical testing in TRPM8-high tumors.
Authors
- Giovanni Bertalot (ORCID: https://orcid.org/0000-0002-4862-7705)
- Orazio Caffo
- Mauro Giulio Papotti (ORCID: https://orcid.org/0000-0002-2713-1700)
- Sabrina Arena (ORCID: https://orcid.org/0000-0002-1318-2494)
- Alberto Brolese (ORCID: https://orcid.org/0000-0002-6362-9055)
- Alessandro Romanel (ORCID: https://orcid.org/0000-0003-4855-8620)
- Sacha Genovesi (ORCID: https://orcid.org/0000-0002-3568-0048)
- Andrea Lunardi (ORCID: https://orcid.org/0000-0001-6218-2565)
- Kate Widmann
- Michela Libergoli (ORCID: https://orcid.org/0000-0003-4329-3221)
- Alberto Bardelli (ORCID: https://orcid.org/0000-0003-1647-5070)
- Kristi Buzo (ORCID: https://orcid.org/0000-0001-8195-5260)
- Francesco Giuseppe Carbone (ORCID: https://orcid.org/0000-0001-8425-9658)
- Alessandro Alaimo (ORCID: https://orcid.org/0000-0002-5888-6268)
- Luca Molinaro (ORCID: https://orcid.org/0000-0001-9030-1998)
- Annalisa Lorenzato (ORCID: https://orcid.org/0000-0002-9324-2337)
- Mattia Barbareschi (ORCID: https://orcid.org/0000-0003-0217-3223)
- Nicole Annesi
- Elisa Marmocchi
Institutions
- University of Trento (IT)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Ospedale Santa Chiara (IT)
- IFOM (IT)
- Candiolo Cancer Institute (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Turin (IT)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1002/1878-0261.70049
- Citations
- 2
- Primary Topic
- Ion Channels and Receptors
- Type
- article
- Field-Weighted Citation Impact
- 2.93
Funders
- Dipartimenti di Eccellenza
- European Commission
- Ministero della Salute
- Università degli Studi di Trento
- Associazione Italiana per la Ricerca sul Cancro
- International Magnesium Institute
- European Regional Development Fund