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.
Malignant pleural mesothelioma (MPM) is a rare, incurable cancer of the mesothelial cells lining the lungs and the chest wall that is mainly caused by asbestos inhalation. The molecular mechanisms of mesothelial carcinogenesis are still unclear despite comprehensive studies of the mutational landscape of MPM, and the most frequently mutated genes BAP1, NF2, CDKN2A, TP53, and TSC1 cannot cause MPM in mice in a standalone fashion. Although KRAS pathway alterations were sporadically detected in older studies employing targeted sequencing, they have been largely undetected by next generation sequencing. We recently identified KRAS mutations and copy number alterations in a significant proportion of MPM patients. Here, we review and analyze multiple human datasets and the published literature to show that, in addition to KRAS, multiple other genes of the KRAS pathway are perturbed in a significant proportion of patients with MPM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.