Co-occurring Mutations of Tumor Suppressor Genes, <i>LATS2</i> and <i>NF2</i> , in Malignant Pleural Mesothelioma

Abstract

<b>Purpose:</b> To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene <i>LATS2</i>, a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis.<b>Experimental Design:</b> Sixty-one MPM primary cultures established in our laboratory were screened for mutations in <i>LATS2</i> Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, Western blot analysis, and reverse phase protein array. Cell proliferation, viability, apoptosis, mobility, and invasion were determined after siRNA knockdown or YAP (verteporfin), mTOR (rapamycin), and mTOR/PI3K/AKT (PF-04691502) inhibitor treatment.<b>Results:</b> The <i>LATS2</i> gene was altered in 11% of MPM by point mutations and large exon deletions. Genetic data coupled with transcriptomic data allowed the identification of a new MPM molecular subgroup, C2^LN, characterized by a co-occurring mutation in the <i>LATS2</i> and <i>NF2</i> genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of <i>LATS2</i> and <i>NF2</i> leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2^LN MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The <i>MOK</i> gene was identified as a potential biomarker of the C2^LN MPM subgroup and PF-04691502 sensitivity.<b>Conclusions:</b> We identified a new MPM molecular subgroup that shares common genetic and transcriptomic characteristics. Our results made it possible to highlight a greater sensitivity to an anticancer compound for this MPM subgroup and to identify a specific potential biomarker. <i>Clin Cancer Res; 23(12); 3191-202. ©2016 AACR</i>.