| Autor: |
Iris Chiara Salaroglio, Dimas Carolina Belisario, Paolo Bironzo, Preeta Ananthanarayanan, Luisa Ricci, Sabrina Digiovanni, Simona Fontana, Francesca Napoli, Alberto Sandri, Chiara Facolmatà, Roberta Libener, Valentina Comunanza, Federica Grosso, Elena Gazzano, Francesco Leo, Riccardo Taulli, Federico Bussolino, Luisella Righi, Mauro Giulio Papotti, Silvia Novello, Giorgio Vittorio Scagliotti, Chiara Riganti, Joanna Kopecka |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Journal of Experimental & Clinical Cancer Research, Vol 41, Iss 1, Pp 1-19 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1756-9966 |
| DOI: |
10.1186/s13046-022-02284-7 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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