Evolution and pharmacological targeting of Hippo pathway inactivation in Mesothelioma

Abstract

Mesothelioma, a cancer caused by asbestos, exhibits marked inter-patient heterogeneity and lacks molecularly targeted therapy. Hippo signalling is an evolutionarily highly conserved pathway that regulates organ size, cell stemness, immune system modulation, and tumorigenesis. The main aims of this work were to: 1. Decipher the evolutionary timing of Hippo pathway inactivation in mesothelioma. To address these gap tumour phylogenies were inferred using multiregional whole exome sequencing of 50 mesotheliomas. To determine the evolutionary trajectories, phylogenetic analysis was conducted. To explore the phenotypes associated with Hippo inactivation RNA sequencing was performed enabling to examine pathways differentially activated by gene set enrichment analysis. 42% of mesotheliomas exhibited bi-allelic inactivation of NF2, which involved both copy number and mutation allelic heterogeneity. Interestingly, patients with transcriptional indicators of YAP/TAZ activation consistently had worse clinical outcomes. 2. Exploit Hippo inactivation as a therapeutic target. In vitro studies were conducted to examine the sensitivities in Hippo wild type versus inactivated pathways in low passage, genotyped mesothelioma cell lines. Drug screening of NF2 wild type versus inactivated primary mesothelioma cell lines, revealed selective sensitivity to CDK7 inhibitors in NF2 inactivated primary mesothelioma cell lines. 3. Understand the role of Hippo inactivation in epithelioid to sarcomatoid mesothelioma transitions. Biphasic mesothelioma tissue microarray was customised with an unequivocal representation of 48 regions from 10 biphasic patients. Geospatial analysis of epithelioid versus sarcomatoid regions indicated that sarcomatoid transformation involves a hypoxia/TGF-b/TEAD/EMT. EMT can could therefore function as a positive selective pressure Hippo pathway inactivation, which happens as a later evolutionary somatic event. In summary, these results suggest that dysregulation of the Hippo pathway contributes to the progression of mesothelioma including spatial transformation and may expose sensitivity to CDK7 inhibition warranting further exploration as a potential targeted therapy in the future.