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

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.

An Integrative Pan-Cancer Analysis Revealing MLN4924 (Pevonedistat) as a Potential Therapeutic Agent Targeting Skp2 in YAP-Driven Cancers

“…It suggested that high SKP2 expression may increase the responsiveness towards MLN4924 in multiple cancer types. This was consistent with the reports that Skp2 drives the sensitivity to MLN4924 in malignant pleural mesothelioma ( Salaroglio et al, 2022 ) and the sensitivity of RB cells to MLN4924 matches their dependency on Skp2 ( Aubry et al, 2020 ). What’s more, it was reported that MLN4924 could inhibit the ubiquitination of Lats1 and 2 mediated by CRL4 DCAF1 , thereby inducing the phosphorylation and inactivation of YAP which led to the inhibition of proliferation in malignant pleural mesothelioma ( Cooper et al, 2017 ).…”

ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades

“…Thus, developing novel neddylation inhibitor agents with improved anticancer efficacy, selectivity, and safety could be a potential future direction for cancer treatment. In addition, an increasing line of evidence suggests that MLN4924 coupled with different anticancer drugs can overcome drug resistance and improve anticancer results [103][104][105][106]. Hence, combined pharmacotherapy or multi-target drugs seem to be promising therapeutic approaches for the future.…”

A MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting

“…MLN4924 has shown anticancer effects in preclinical adult and pediatric tumor models 17,[51][52][53][54] and good tolerability in Phase I clinical trials as monotherapy and in combination studies in adult cancer patients 40,[55][56][57][58]. Two Phase I studies are ongoing using this agent in combinatorial approaches also in the pediatric cancer setting involving patients with leukemia/lymphoma (NCT03349281, NCT03813147).…”