Abstract
Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM. The NF2 gene encodes merlin, a protein that regulates multiple cell-signaling cascades including the Hippo pathway. MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM. Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes, including prooncogenic CCDN1 and CTGF, have also been shown to enhance the malignant phenotypes of MM cells. Together, these data indicate the Hippo pathway as a therapeutic target for the treatment of MM, and support the development of new strategies to effectively target the activation status of YAP1/TAZ as a promising therapeutic modality for this formidable disease.
Highlights
Malignant mesothelioma (MM) constitutes an aggressive neoplasm that arises primarily from pleura or peritoneum serosal cells, such that almost 80% of cases are pleural in origin [1,2]
MMs are pathologically classified as either epithelioid, sarcomatoid, or biphasic [5]. As they are often refractory to conventional therapies, they often incur a poor patient prognosis, with the median overall survival (OS) time for patients with malignant pleural mesothelioma (MPM) being 12–18 months after diagnosis, regardless of trimodality therapy consisting of induction chemotherapy followed by surgery and post-operative radiation therapy [6]
11% of 61 MPM primary cultures were found to harbor point mutations and/or large exon deletions that inactivated LATS2 [62]. These findings indicate that neurofibromatosis type 2 (NF2) and LATS2 mutations can be coincident in a given MM tumor
Summary
Malignant mesothelioma (MM) constitutes an aggressive neoplasm that arises primarily from pleura or peritoneum serosal cells, such that almost 80% of cases are pleural in origin [1,2]. A recent phase-II trial found that an angiokinase inhibitor termed nintedanib, which targets vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors (FGFRs), and Src and Abl-kinase signaling, improved the progression free survival (PFS) time for patients with MPM when administered in combination with pemetrexed and cisplatin [19]. This effect is currently being confirmed via an ongoing phase-III trial [19]. Society of Clinical Oncology Clinical Practice Guidelines provided evidence-based recommendations for the diagnosis and staging of patients with MPM, as well as for the subsequent administration of chemotherapeutic, surgical cytoreduction, radiation, and/or multimodal therapies [34]
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