RT Journal Article
SR Electronic
T1 <em>KRAS</em> signalling in malignant pleural mesothelioma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.22.350850
DO 10.1101/2020.10.22.350850
A1 Marazioti, Antonia
A1 Blanquart, Christophe
A1 Krontira, Anthi C.
A1 Pepe, Mario A. A.
A1 Hackl, Caroline M.
A1 Iliopoulou, Marianthi
A1 Lamort, Anne-Sophie
A1 Koch, Ina
A1 Lindner, Michael
A1 Hatz, Rudolph A.
A1 Wagner, Darcy E.
A1 Papadaki, Helen
A1 Antimisiaris, Sophia G.
A1 Psallidas, Ioannis
A1 Spella, Magda
A1 Giopanou, Ioanna
A1 Lilis, Ioannis
A1 Grégoire, Marc
A1 Stathopoulos, Georgios T.
YR 2020
UL http://biorxiv.org/content/early/2020/10/23/2020.10.22.350850.abstract
AB 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 like 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 significant proportion of human MPM harbour point mutations and copy number alterations in the KRAS proto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiating KRASG12D 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 mutations likely play an important and underestimated role in MPM, which warrants further exploration.