KRASsignalling in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes likeBAP1, NF2, CDKN2A, andTP53, 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 significant proportion of human MPM harbour point mutations and copy number alterations in theKRASproto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutantKRASG12Din the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiatingKRASG12Dlesions, secondaryBap1alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate thatKRASmutations likely play an important and underestimated role in MPM, which warrants further exploration.