Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

Marqués, Miriam; Tranchant, Robin; Risa-Ebrí, Blanca; Suárez-Solís, María L.; Fernández, Luís; Pau, Enrique Carrillo de Santa; Pozo, Natalia del; Villarreal, Jaime Martínez de; Meiller, Clément; Allory, Yves; Blum, Yuna; Pirker, Christine; Hegedűs, Balázs; Barry, Simon T.; Carnero, Amancio; Berger, Walter; Jean, Didier; Real, Francisco X.

doi:10.1158/0008-5472.can-19-1633

Cited by 20 publications

(17 citation statements)

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“…Indeed, ROS can directly lead to the inactivation of PTEN, a lipid phosphatase involved in the negative regulation of this pathway, through the oxidation of its cysteine residues [20]. Recently, loss of PTEN expression has been reported in a high percentage of human sarcomatoid MPM as compared with other subtypes [15]. In addition, components of the PI3K/AKT/mTOR pathway have been found to be deregulated in MPM, in particular mutations in the catalytic subunit of PI3K have been frequently detected in MPM patients and associated to disease progression [21,22].…”

Section: Discussionmentioning

confidence: 99%

“…These effects were observed under both normoxic and hypoxic conditions. It is worth noting that both MSTO-211H and H2052 cells were positive for PTEN protein (a negative regulator of AKT activation frequently lost in tumors including MPM [15]) and its expression was not affected by the drug treatments.…”

Section: The Combined Treatment With Cdk4/6 and Pi3k/mtor Inhibitors mentioning

confidence: 99%

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Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Bonelli

Terenziani

Zoppi

et al. 2020

IJMS

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Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

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Section: Discussionmentioning

confidence: 99%

Section: The Combined Treatment With Cdk4/6 and Pi3k/mtor Inhibitors mentioning

confidence: 99%

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Bonelli

Terenziani

Zoppi

et al. 2020

IJMS

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“…Our research also shows that MEK2 also plays an important role in the proliferation and migration of ccRCC cells. Studies have reported that treatment of cells with AZD6244 for a short time reduced the phosphorylation level of MEK1/2 instead of regulating the protein expression of MEK1/2 [ 34 , 35 ]. However, our results showed that AZD6244 decreased MEK2 protein level (Fig.…”

Section: Discussionmentioning

confidence: 99%

Myc-associated zinc-finger protein promotes clear cell renal cell carcinoma progression through transcriptional activation of the MAP2K2-dependent ERK pathway

Ren

Zhao

et al. 2021

Cancer Cell Int

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Background The dysfunction of myc-related zinc finger protein (MAZ) has been proven to contribute to tumorigenesis and development of multiple cancer types. However, the biological roles and clinical significance of MAZ in clear cell renal carcinoma (ccRCC) remain unclear. Methods MAZ expression was examined in ccRCC and normal kidney tissue by quantitative real-time PCR and Western blot. Statistical analysis was used to evaluate the clinical correlation between MAZ expression and clinicopathological characteristics to determine the relationship between MAZ expression and the survival of ccRCC patients. The biological roles of MAZ in cells were investigated in vitro using MTT and colony assays. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to investigate the relationship between MAZ and its potential downstream signaling molecules. Results MAZ expression is elevated in ccRCC tissues, and higher levels of MAZ were correlated with poor survival of patients with ccRCC. MAZ upregulation elevates the proliferation ability of ccRCC cells in vitro, whereas silencing MAZ represses this ability. Our results further reveal that MAZ promotes cell growth, which is dependent on ERK signaling. Importantly, we found that MAZ positively regulates MAP2K2 expression in ccRCC cells. Mechanistically, MAZ binds to the MAP2K2 promoter and increases MAP2K2 transcription. Furthermore, MAP2K2 levels were shown to be increased in ccRCC tissues and to be associated with a poor prognosis of ccRCC patients. MAP2K2 upregulation activates the ERK signaling pathway and promotes ccRCC progression. Conclusion These results reveal that the MAZ/MAP2K2/ERK signaling axis plays a crucial role in promoting ccRCC progression, which suggests the potential therapeutic utility of MAZ in ccRCC.

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“…Changes in AS events are frequently observed in cancer and are beginning to be recognized as critical signatures of tumor development, differentiation and treatment [ 14 ]. MM is an aggressive tumor with high chemoresistance and poor survival [ 34 ]. Due to the low incidence of MM, there has been little progress in the knowledge of the molecular mechanisms associated with MM.…”

Section: Discussionmentioning

confidence: 99%

Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma

Lai

Yang

2021

BMC Cancer

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Background Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM. Methods We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan–Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs). Results A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM. Conclusion Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.

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Combined MEK and PI3K/p110β Inhibition as a Novel Targeted Therapy for Malignant Mesothelioma Displaying Sarcomatoid Features

Cited by 20 publications

References 50 publications

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Myc-associated zinc-finger protein promotes clear cell renal cell carcinoma progression through transcriptional activation of the MAP2K2-dependent ERK pathway

Systemic characterization of alternative splicing related to prognosis and immune infiltration in malignant mesothelioma

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