Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients

Cedrés, S.; Iranzo, Patricia Izquierdo; Callejo, Ana; Pardo, Núria; Navarro, Alejandro; Martinez-Martí, Alex; Gómez-Abecia, Sara; Zucchiatti, A C; Sansano, Irene; Enguita, Ana B.; Miquel, Josep M.; Viaplana, Cristina; Dienstmann, Rodrigo; Paz‐Ares, Luis; Felip, Enriqueta

doi:10.1007/s12094-019-02275-9

Cited by 12 publications

(9 citation statements)

References 45 publications

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“…In this setting, the inhibition of the SCF complex promotes the induction of ICD, particularly in combination with immune-checkpoint inhibitors [ 32 ]. This mechanism does not seem the case of MPM that, differently from colorectal cancer, is characterized by a low genomic instability [ 33 ]. Indeed, neither cisplatin nor MLN4924, alone or combined, increased the TMB, notwithstanding they both induce DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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

Belisario

Bironzo

Ananthanarayanan

et al. 2022

J Exp Clin Cancer Res

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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.

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Section: Discussionmentioning

confidence: 99%

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

Belisario

Bironzo

Ananthanarayanan

et al. 2022

J Exp Clin Cancer Res

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“…According to the low TMB, microsatellite instability and deficiency of DNA mismatch repair system proteins (dMMR) (MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), MutL Homolog 1 (MLH1)) due to gene mutation or epigenetic silencing, have been found in a small subset of MPM [ 23 , 24 , 25 ]. In this scenario of a low mutational burden, epigenetic regulation is considered to significantly contribute to the malignant mesothelial transformation.…”

Section: Introductionmentioning

confidence: 99%

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

Cersosimo

Barbarino

Lonardi

et al. 2021

Cancers

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Several studies have reported that cellular and soluble components of the tumor microenvironment (TME) play a key role in cancer-initiation and progression. Considering the relevance and the complexity of TME in cancer biology, recent research has focused on the investigation of the TME content, in terms of players and informational exchange. Understanding the crosstalk between tumor and non-tumor cells is crucial to design more beneficial anti-cancer therapeutic strategies. Malignant pleural mesothelioma (MPM) is a complex and heterogenous tumor mainly caused by asbestos exposure with few treatment options and low life expectancy after standard therapy. MPM leukocyte infiltration is rich in macrophages. Given the failure of macrophages to eliminate asbestos fibers, these immune cells accumulate in pleural cavity leading to the establishment of a unique inflammatory environment and to the malignant transformation of mesothelial cells. In this inflammatory landscape, stromal and immune cells play a driven role to support tumor development and progression via a bidirectional communication with tumor cells. Characterization of the MPM microenvironment (MPM-ME) may be useful to understand the complexity of mesothelioma biology, such as to identify new molecular druggable targets, with the aim to improve the outcome of the disease. In this review, we summarize the known evidence about the MPM-ME network, including its prognostic and therapeutic relevance.

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“…Hypermutation and genomic instability resulting from defective DNA mismatch repair (MMR) is infrequent in MM [11]. Instead, major genomic alterations affect a series of tumor-suppressor genes in human MM, e.g., the BRCA1-associated deubiquitylase (BAP1), the cyclin-dependent kinase inhibitor 2A/B (CDKN2AB), neurofibromatosis type 2/moesin-ezrin-radixin-like protein (NF2/Merlin), and tumor protein 53 (TP53).…”

Section: Oncogenesis Of Mesothelioma Occurs At Low Tumor Mutational Burdenmentioning

confidence: 99%

“…Hypermutation and genomic instability resulting from defective DNA mismatch repair (MMR) is infrequent in MM [11]. Instead, major genomic alterations affect a series of The different cancer types are indicated on the X-axis: skin cutaneous melanoma (SKCM), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), bladder urothelial carcinoma (BLCA), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), stomach adenocarcinoma (STAD), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), rectum adenocarcinoma (READ), cervical squamous cell carcinoma and end cervical adenocarcinoma (CESC), liver hepatocellular carcinoma (LIHC), uterine corpus endometrial carcinoma (UCEC), ovarian serous cystadenocarcinoma (OV), kidney renal papillary cell carcinoma (KIRP), glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), uterine carcinosarcoma (UCS), sarcoma (SARC), breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), brain lower-grade glioma (LGG), adrenocortical carcinoma (ACC), prostate adenocarcinoma (PRAD), mesothelioma (MESO, in red), kidney chromophobe (KICH), testicular germ cell tumors (TGCT), thymoma (THYM), acute myeloid leukemia (LAML), uveal melanoma (UVM), thyroid carcinoma (THCA) and pheochromocytoma and paraganglioma (TCPG).…”

Section: Oncogenesis Of Mesothelioma Occurs At Low Tumor Mutational Burdenmentioning

confidence: 99%

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

Brossel

Fontaine

Hoyos

et al. 2021

Cancers

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Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.

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Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients

Cited by 12 publications

References 45 publications

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

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

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

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