Genomic characterization and high-throughput therapeutic screening of malignant mesothelioma to reveal novel tumor dependencies.

Abstract

7581 Background: Clinical trials of targeted therapeutics in mesothelioma have demonstrated limited efficacy. It has been suggested that combinations of targeted agents may be more effective in this disease, but given the unknown status of tractable oncogenic mutations it has been difficult to ascertain which key signalling nodes drive these tumours that may lend themselves to therapeutic intervention. We therefore aimed to characterise a representative panel of mesothelioma cell lines at the genomic level, and then determine critical “nodes” utilising a high throughput screen of targeted agents. Methods: 19 mesothelioma cell lines and 6 mesothelioma primary tumour early passage lines underwent Illumina whole exome sequencing and copy number analysis. In parallel a high throughput screen was performed utilising a panel of targeted therapeutics enabling each mesothelioma to be screened across 48 compounds. Efficacy was confirmed in 3D spheroid culture. Results: Exome sequencing of the mesothelioma panel revealed mutations in tumour suppressor genes previously described in mesothelioma including NF2, as well as previously unreported mutations in this disease affecting histone modifying genes MLL2 and SETD2. Notably an absence of mutated “driver” oncogenes was observed. High throughput screening demonstrated limited activity for most small molecule inhibitors as single agents. However, despite an absence of mutations in PIK3CAor related genes, PI3K/mTORC inhibition had the broadest single agent efficacy. Conclusions: We demonstrate that mutations in cell lines are similar to those found in patient-derived tumours implying fidelity at the genomic level. Mesotheliomas harbour multiple mutations in tumour suppressors, but lack commonly tractable oncogenic mutations which may explain poor efficacy seen in clinical trials to date. We further demonstrate that PI3K may represent a critical node therapeutically that may be useful in combinatorial approaches.