SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma

Our plain-English summary of SKP2 drives the sensitivity to neddylation inhibitors and cisplatin in malignant pleural mesothelioma, by I.C. Salaroglio, D.C. Belisario, P. Bironzo, et al (Journal of Experimental & Clinical Cancer Research, 2022).

The study

• Authors: I.C. Salaroglio, D.C. Belisario, P. Bironzo, P. Ananthanarayanan, L. Ricci, S. Digiovanni, S. Fontana, F. Napoli, A. Sandri, C. Facolmatà, R. Libener, V. Comunanza, F. Grosso, E. Gazzano, F. Leo, R. Taulli, F. Bussolino, L. Righi, M.G. Papotti, S. Novello, G.V. Scagliotti, C. Riganti, J. Kopecka
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2022;41(1):75
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2022. The Author(s).

In plain English

This laboratory study of malignant pleural mesothelioma treatment included a small patient analysis. It did not study asbestos exposure. The authors tested MLN4924 (pevonedistat), alone and with the chemotherapy drug cisplatin, on patient-derived mesothelioma cells and on mesothelioma tumors in mice. In initial tests on 6 cultures, MLN4924 alone did not increase necrosis or reduce viability or proliferation, though it stalled cell division in some types; the combination outperformed cisplatin alone. Combination index values of 0.11098, 0.08012 and 0.07263 in epithelioid, biphasic and sarcomatous cells indicated strong synergy. In mice, the combination produced smaller tumors and more tumor-infiltrating immune cells. Mouse blood tests showed no liver, kidney or heart toxicity from any treatment. In 6 of 19 patient cultures the combination added no benefit. Comparing the 3 best- and 3 worst-responding cultures, responders had higher SKP2 levels. Cells made to overproduce SKP2 resisted cisplatin more. Among 19 platinum-treated patients, the 10 with low SKP2 had longer time to progression and overall survival than the 9 with high SKP2. The authors concluded the combination should be clinically tested in platinum-unresponsive patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using patient-derived mesothelioma cell cultures and a mouse tumor model, plus a retrospective analysis of patients treated with platinum chemotherapy
• Who was studied: 23 primary human malignant pleural mesothelioma cultures (13 epithelioid, 5 biphasic, 5 sarcomatous) were obtained during diagnostic thoracoscopies at hospitals in Orbassano, Torino and Alessandria, Italy. The study also used female BALB/C mice implanted with murine AB1 mesothelioma cells (4 groups of 10). The patient analysis covered 19 patients who received carboplatin or cisplatin as first-line treatment.
• Exposure: Drug treatments, not asbestos. In cells: 50 μM cisplatin, 0.2 μM MLN4924 (a neddylation inhibitor), or both. In mice: 5 mg/kg cisplatin once a week and/or 25 mg/kg MLN4924 5 days a week for 3 weeks.
• Main results:
  • In the initial tests on 6 patient-derived mesothelioma cultures, MLN4924 alone did not increase necrosis (measured by LDH release) or decrease cell viability or proliferation. Cisplatin did.
  • MLN4924 alone did cause cell-cycle arrest: in S- and G2/M-phase in epithelioid cells, and in S-phase in biphasic cells.
  • MLN4924 alone caused DNA fragmentation in biphasic and sarcomatous cells. Cisplatin caused it in all histotypes, and the combination was more potent than either drug alone.
  • In patient-derived mesothelioma cells, the cisplatin plus MLN4924 combination was more active than cisplatin alone, regardless of histotype.
  • The combination index of cisplatin and MLN4924 was 0.11098 in epithelioid, 0.08012 in biphasic and 0.07263 in sarcomatous cells. The authors described this as a very strong synergistic effect.
  • In mice, the combination gave lower tumor growth and smaller excised tumors.
  • Based on blood tests in the mice, none of the treatments caused liver, kidney or heart toxicity.
  • In mice, the combination was the only treatment that significantly increased tumor-infiltrating CD4+ and CD8+ T-lymphocytes.
  • In lab co-culture experiments, activated cytotoxic CD8+CD107a+ T-cells doubled from 10% with untreated mesothelioma cells to 20% with combination-treated cells.
  • Among the 19 cultures from platinum-treated patients, adding MLN4924 did not enhance cisplatin's effect in 6 (non-responders).
  • The 3 top responder cultures had higher SKP2 mRNA and protein than the 3 top non-responder cultures. One culture of each histotype was chosen for each group.
  • Mesothelioma cells engineered to overexpress SKP2 were more resistant to cisplatin than control cells.
  • In knockout experiments, low SKP2 levels were associated with higher sensitivity to cisplatin.
  • Among the 19 patients treated with platinum first-line, the low-SKP2 group (10 patients) had significantly longer time to progression and higher overall survival than the high-SKP2 group (9 patients).
  • For the high versus low SKP2 comparison, the reported p values were less than 0.016 for time to progression and less than 0.044 for overall survival.
• The authors' conclusion: The authors concluded that combining neddylation inhibitors with cisplatin should be clinically investigated in patients not responding to platinum-based chemotherapy. They also proposed SKP2 as a potential stratification marker.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Pemetrexed (Alimta), Systemic Therapy, Chemotherapy, BAP1, Apoptosis.

Related studies

• Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma — J. Kopecka, I.C. Salaroglio, et al. (2018)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• 2-Deoxy-glucose Enhances the Effect of Cisplatin and Pemetrexed in Reducing Malignant Pleural Mesothelioma Cell Proliferation But Not Spheroid Growth — I. Gerogianni, E. Pitaraki, et al. (2019)
• Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model — F. Sonvico, S. Barbieri, et al. (2018)
• Dual HDAC and PI3K Inhibitor CUDC-907 Inhibits Growth of Pleural Mesothelioma: The Impact of Cisplatin Sensitivity and Myc Expression — L. Hegedüs, S. Qaisieh, et al. (2025)
• A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma — E.M.J. van Brummelen, E. Levchenko, et al. (2020)

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