Therapeutic vulnerabilities exposed by the 9p21 loss identified through multiparametric drug screening inform rational combination strategies.

Bevilacqua, Riccardo; Gasperini, Paola; Cantore, Thomas; Macedo-Silva, Catarina; Pancher, Michael; Radic, Martina; Yue, Haiyan; Quaini, Orsetta; Fedrizzi, Tarcisio; Gatto, Pamela; Seiler, Roland; Kiss, Bernhard; Adami, Valentina; Lorenzin, Francesca; Kruithof-de Julio, Marianna; Morris Faltas, Bishoy; Demichelis, Francesca

doi:10.48620/97075

Therapeutic vulnerabilities exposed by the 9p21 loss identified through multiparametric drug screening inform rational combination strategies.

DOI

10.48620/97075

Publisher DOI

10.1038/s41698-026-01434-w

PubMed ID

42000949

Abstract

Homozygous loss of the 9p21 locus encompassing CDKN2A, CDKN2B, and MTAP is the most frequent copy number alteration across tumor types, making it a promising target for precision medicine strategies. To explore drug vulnerabilities exposed by this loss, we generated 9p21 locus isogenic bladder cancer (BLCA) cell models to perform a multiparametric drug screen, testing 2,349 compounds. We identified cytarabine and methotrexate as significantly more effective in the 9p21 compromised BLCA cells. Analysis of morphological alterations further supported a genotype-specific activity of nucleoside analogs, nominating gemcitabine as a drug with greater efficacy in this context. To further exploit MTAP loss, we explored drug combinations targeting MTAP synthetic lethal partners, PRMT5 and MAT2A. Synergy between cytarabine and inhibitors of PRMT5 (MRTX1719) and MAT2A (AG-270) was mediated by a differential activation of DNA damage and replication stress markers, suggesting an exploitable vulnerability. In fact, rational drug combinations with ATR/CHK1 pathway inhibitors increased efficacy while maintaining 9p21-specificity. Finally, we confirmed the effectiveness of these combinations in cell models of pancreatic adenocarcinoma and pleural mesothelioma, two tumor types with high prevalence of MTAP loss and, most notably, in bladder cancer patient-derived organoids, underscoring the strong translational potential of our findings.

Date Issued

2026-04-18

Publication Type

Article

Language(s)

en

Author(s)

Bevilacqua, Riccardo
Gasperini, Paola
Cantore, Thomas
Macedo-Silva, Catarina	Department for BioMedical Research, Forschungsgruppe Urologie
Pancher, Michael
Radic, Martina	Department for BioMedical Research, Forschungsgruppe Urologie
Yue, Haiyan	Department for BioMedical Research (DBMR)
Quaini, Orsetta
Fedrizzi, Tarcisio
Gatto, Pamela
Seiler, Roland	Department for BioMedical Research (DBMR)
	Clinic of Urology
Kiss, Bernhard	Clinic of Urology
	Department for BioMedical Research (DBMR)
Adami, Valentina
Lorenzin, Francesca
Kruithof-de Julio, Marianna	Department for BioMedical Research, Forschungsgruppe Urologie
	Clinic of Urology
Morris Faltas, Bishoy
Demichelis, Francesca

Additional Credits

Clinic of Urology

Department for BioMedical Research (DBMR)

Department for BioMedical Research, Forschungsgruppe Urologie

Journal

npj Precision Oncology

Publisher

Nature Research

ISSN

2397-768X

Access(Rights)

open.access

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