Frequent NF2 Inactivation in Mesothelioma: How Can We Treat Mesothelioma with Targeted Therapies for Molecular Aberrations?

Abstract

AbstractThe NF2 gene was initially identified as a causative gene for neurofibromatosis type 2 cancer syndrome. Soon thereafter, NF2 was shown to be frequently mutated in malignant mesothelioma (MM). Recent genomic profiling confirmed that approximately 40% of mesothelioma cases show inactivating alterations of NF2. NF2 encodes moesin–ezrin–radixin-like (merlin), a protein that regulates multiple cell-signaling cascades including the Hippo tumor-suppressive signaling pathway. MMs also exhibit genetic or epigenetic inactivation of Hippo pathway components including MST1/2 and LATS1/2, which indicates that merlin–Hippo pathway dysregulation plays a key role in MM development and progression. Hippo pathway inactivation leads to the constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes include prooncogenic cell cycle promoter genes such as CCDN1 and growth factor/cytokine genes including CTGF and IL1B. Meanwhile, YAP1/TAZ may also act as a tumor suppressor under specific cellular contexts; for example, YAP1 promotes regulated cell death known as ferroptosis. These data indicate that the merlin (NF2)–Hippo pathway may be a therapeutic target for the treatment of MM and support the development of new strategies to effectively kill MM cells depending on the dysregulated (or regulated) status of this pathway.KeywordsMalignant mesotheliomaNF2Hippo pathwayYAP1/TAZ