BIRC3/CAV1 co-expression drives GBM aggressiveness as a prognostic signature and therapeutic vulnerability
Glioblastoma (GBM) is an incurable tumor where temozolomide (TMZ) resistance limits survival, even in MGMT-methylated patients. To improve stratification, we used NAD(P)H-FLIM to profile TMZ response in 35 patient-derived explants, integrating these data with transcriptomic and functional analyses. We identified BIRC3 and CAV1 upregulation in resistant tumors and investigated their parallel yet functionally cooperative role in driving an aggressive, therapy-resistant phenotype. In silico survival analyses demonstrated that BIRC3 and CAV1 act as independent prognostic factors whose additive, non-linear effects robustly stratify patient survival beyond MGMT status, defining a subgroup with <7% 24-month survival. Importantly, BIRC3/cIAP2-driven resistance proved targetable; the IAP antagonist AZD5582 restored TMZ sensitivity by unlocking the apoptotic execution phase, thereby inducing cell death in resistant GBM models in vitro and ex vivo. Our findings establish the BIRC3/CAV1 axis as a key prognostic signature and therapeutic vulnerability in GBM, offering a new path for precision oncology strategies.
Authors
- Francesca Lessi (ORCID: https://orcid.org/0000-0002-3346-4296)
- Francesco Pasqualetti (ORCID: https://orcid.org/0000-0002-0788-1205)
- Manuel Giacomarra
- Andrea Marranci (ORCID: https://orcid.org/0000-0002-8334-8795)
- Francesco Pieri (ORCID: https://orcid.org/0000-0003-4456-8581)
- Michele Menicagli
- Chiara Maria Mazzanti (ORCID: https://orcid.org/0000-0002-7249-9221)
- Carlo Gambacciani (ORCID: https://orcid.org/0000-0001-9271-6070)
- Sara Franceschi (ORCID: https://orcid.org/0000-0002-4246-4407)
- Orazio Santo Santonocito (ORCID: https://orcid.org/0000-0002-1071-7166)
- Paolo Aretini (ORCID: https://orcid.org/0000-0003-1075-4319)
- Gianmarco Ferri (ORCID: https://orcid.org/0000-0002-4341-8920)
- Alberto Pïcca (ORCID: https://orcid.org/0000-0001-7807-5393)
- Federico Villanacci
- Mariangela Morelli (ORCID: https://orcid.org/0000-0001-8796-4037)
- Aldo Pastore
- Anna Luisa Di Stefano
- Francesca Di Lorenzo
- Marc Sanson
- Marco Krengli
- Nicola Montemurro
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Padua (IT)
- Inserm (FR)
- Scuola Normale Superiore (IT)
- Scuola Superiore Sant'Anna (IT)
- Fondazione Pisa (IT)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Istituto Oncologico Veneto (IT)
- Pitié-Salpêtrière Hospital (FR)
- Institut du Cerveau (FR)
- Azienda Ospedaliera Universitaria Pisana (IT)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2026-04-13
- DOI
- https://doi.org/10.1038/s41420-026-03112-z
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Associazione Italiana per la Ricerca sul Cancro