MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma

Our plain-English summary of MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma, by H. Yang, Y. Gao, D. Xu, et al (Cell Death Discovery, 2023).

The study

• Authors: H. Yang, Y. Gao, D. Xu, K. Xu, S.Q. Liang, Z. Yang, A. Scherz, S.R.R. Hall, S. Forster, S. Berezowska, F. Yao, A.F. Ochsenbein, T.M. Marti, G.J. Kocher, R.A. Schmid, P. Dorn, R.W. Peng
• Journal: Cell Death Discovery
• Published: 2023;9(1):55
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.

© 2023. The Author(s).

In plain English

This laboratory study examined the RAS/MAPK signaling pathway, which includes the protein MEK1, in malignant pleural mesothelioma. It did not study asbestos exposure; the authors cited earlier work linking asbestos to reactive oxygen species and MAPK signaling as motivation. The authors analyzed public datasets and studied mesothelioma cell lines, cells from one patient's tumor, and tumors grown in mice. Among 32 cancer types, tumors from 61 mesothelioma patients showed the highest average level of activated MEK1. Reducing MEK1 slowed the growth of mesothelioma cells. In a public cohort, high MEK activity was associated with poorer survival. The MEK inhibitor trametinib alone delayed but did not stop tumor growth in mice. Trametinib combined with the PARP inhibitors olaparib or talazoparib had synergistic effects on the cells. In separate experiments, trametinib plus olaparib raised levels of reactive oxygen species. In mice, the combination had significantly greater anti-tumor effects than either drug alone. The authors concluded the combination warrants clinical investigation in mesothelioma patients. They noted that some correlations lacked experimental validation and mechanistic work used only two cell lines.

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: analysis of public patient datasets (protein, gene-expression and survival data), plus cell culture experiments and mouse xenograft experiments
• Who was studied: Public protein data on tumors from 61 malignant pleural mesothelioma patients compared with 32 cancer types; TCGA mesothelioma patient cohort; mesothelioma cell lines (H28, H2452, H2052, MESO-1, MSTO-211H, JL-1); a primary cell culture (BE261T) from the surgically removed tumor of a 67-year-old man; and mice carrying grafted tumors
• Exposure: No asbestos exposure was studied. Asbestos appears only in the authors' citation of earlier work as motivation. The study tested drugs: the MEK inhibitor trametinib and the PARP inhibitors olaparib and talazoparib, alone and in combination. It also tested genetic reduction of MEK1.
• Main results:
  • Among 32 cancer types, mesothelioma tumors from 61 patients showed the highest average level of activated MEK1 (p-MEK1)
  • In mesothelioma cells, reducing MEK1 (alone or together with MEK2) significantly inhibited proliferation, to varying degrees
  • In the TCGA cohort of mesothelioma patients, high MEK activity was associated with poor survival
  • In mice carrying patient-derived tumors, trametinib alone delayed but did not stop tumor growth
  • In mesothelioma cells, combining the MEK inhibitor with PARP inhibitors (olaparib or talazoparib) had synergistic anti-proliferative effects. The combination showed no synergism in fibroblast cells from normal human lung.
  • In the reactive oxygen species experiments (trametinib 0.5 µM with a PARP inhibitor at 5 µM, olaparib where named), the combination significantly increased reactive oxygen species in all mesothelioma cells tested. The antioxidant N-acetyl cysteine reduced the effects of trametinib plus olaparib.
  • In mice, the combination showed significantly greater anti-tumor effects than the single drugs in MESO-1, MSTO-211 and H2452 xenografts and in the BE261T patient-derived xenograft
• The authors' conclusion: The authors concluded that the RAS/MAPK pathway is hyperactive in mesothelioma. Because MEK and PARP inhibitors are clinically approved, they concluded that the combination warrants clinical investigation in mesothelioma patients.
• Limitations the authors state:
  • Some correlative analyses lacked experimental validation, and the mechanistic studies relied on only two mesothelioma cell lines
  • The relationship between MEK inhibition and the DNA-repair (homologous recombination) defect was not explored in detail in the mesothelioma model

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Carcinogenesis, Reactive Oxygen Species (ROS), Apoptosis, Histological Subtype.

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