KRAS signaling in malignant pleural mesothelioma

• Published in: EMBO molecular medicine Vol. 14; no. 2; pp. e13631 - n/a
• Main Authors: Marazioti, Antonia, Krontira, Anthi C, Behrend, Sabine J, Giotopoulou, Georgia A, Ntaliarda, Giannoula, Blanquart, Christophe, Bayram, Hasan, Iliopoulou, Marianthi, Vreka, Malamati, Trassl, Lilith, Pepe, Mario A A, Hackl, Caroline M, Klotz, Laura V, Weiss, Stefanie A I, Koch, Ina, Lindner, Michael, Hatz, Rudolph A, Behr, Juergen, Wagner, Darcy E, Papadaki, Helen, Antimisiaris, Sophia G, Jean, Didier, Deshayes, Sophie, Grégoire, Marc, Kayalar, Özgecan, Mortazavi, Deniz, Dilege, Şükrü, Tanju, Serhan, Erus, Suat, Yavuz, Ömer, Bulutay, Pınar, Fırat, Pınar, Psallidas, Ioannis, Spella, Magda, Giopanou, Ioanna, Lilis, Ioannis, Lamort, Anne‐Sophie, Stathopoulos, Georgios T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.02.2022; EMBO Press; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: Animal models; Animals; Asbestos; BAP1; Cancer; Cancer and Oncology; Cancer och onkologi; Cell cycle; Cell lines; Clinical Medicine; Copy number; Datasets; Ectopic expression; EMBO03; EMBO35; Gene deletion; Gene expression; Genomes; Genomics; Humans; K-Ras protein; Klinisk medicin; KRAS; Life Sciences; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Mesothelioma; Mesothelioma - genetics; Mesothelioma - pathology; Mesothelioma, Malignant - genetics; Mesothelioma, Malignant - pathology; Mesothelium; Mice; Mutation; NF2; p53 Protein; Pleural cavity; Pleural effusion; Pleural Neoplasms - genetics; Pleural Neoplasms - pathology; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Signal Transduction; TP53; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; KRAS; NF2; asbestos; TP53; BAP1; Respiratory System; TP53 Subject Categories Cancer
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202013631

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos‐exposed individuals and rapidly leads to death. MPM harbors loss‐of‐function mutations in BAP1 , NF2 , CDKN2A , and TP53 , but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS G12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS G12D lesions, secondary Bap1 alterations, and human MPM‐like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration. Synopsis Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available. Activating mutations, amplifications, and transcriptional activation of KRAS alone or in combination with inactivating alterations of TP53 are found in 20% of 86 MPM patients from the TCGA dataset. KRAS mutations alone or in combination with TP53 loss are corroborated in 40–50% of 35 newly reported MPM patients and of 33 established MPM cell lines. Mesothelial‐restricted ectopic expression of KRASG12D alone or in combination with deletion of the murine TP53 genes are shown to trigger epithelioid or biphasic MPM, respectively, with 100% penetrance. Three MPM cell lines are provided, which feature the causative KRAS and TP53 mutations but also secondary mutations in the mouse BAP1 gene, as well as a human MPM‐like transcriptome. Transgenic and transplantable MPM models for hypothesis testing and drug triage are provided and the prototype KRAS inhibitor deltarasin is shown to block MPM development in mice by 76%. Graphical Abstract Human malignant pleural mesothelioma (MPM) is a devastating occupational cancer that kills more than 200,000 individuals annually. Some MPM harbor mutations of the KRAS proto‐oncogene, but their functional significance is unknown and experimental models for these MPM are not available.