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- Title
SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma.
- Authors
Salaroglio, Iris Chiara; Belisario, Dimas Carolina; Bironzo, Paolo; Ananthanarayanan, Preeta; Ricci, Luisa; Digiovanni, Sabrina; Fontana, Simona; Napoli, Francesca; Sandri, Alberto; Facolmatà, Chiara; Libener, Roberta; Comunanza, Valentina; Grosso, Federica; Gazzano, Elena; Leo, Francesco; Taulli, Riccardo; Bussolino, Federico; Righi, Luisella; Papotti, Mauro Giulio; Novello, Silvia
- Abstract
Background: The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results. Methods: Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat. Results: In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival. Conclusions: We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.
- Subjects
CISPLATIN; PEMETREXED; UBIQUITIN-conjugating enzymes; MESOTHELIOMA; ENDOPLASMIC reticulum; PROTEASOME inhibitors
- Publication
Journal of Experimental & Clinical Cancer Research (17569966), 2022, Vol 41, Issue 1, p1
- ISSN
1756-9966
- Publication type
Article
- DOI
10.1186/s13046-022-02284-7