therapeutic pathways in malignant mesothelioma

Abstract Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. It shows limited responses to all treatments. Although 20% of tumours may transiently regress after checkpoint immunotherapy1,2, predictors of response are unknown. The molecular landscape is of low complexity but recurrent lesions have not yet defined effective therapeutic targets. In order to comprehensively map genomic alterations, we combined copy-number analysis from SNP arrays with targeted sequencing of tumours from 121 patients. We found previously unrecognised deletions in the tumour suppressor RB1 in 26% of cases. These combined with CDKN2A and TP53 lesions affected the RB tumour suppressor pathway in 65% of tumours. We show here therapeutic avenues downstream of RB1 by finding micromolar half maximal inhibitory concentrations (IC50s) of PLK1, CHEK1 and Aurora Kinase inhibitors in MPM cell lines. Non-overlapping defects in Hippo pathways (RASSF7 amplification, NF2, LATS1 and LATS2 mutations) were present in 48% of tumours, accompanied by micromolar IC50s to the YAP1 inhibitor Verteporfin. Loss of a 240Kb locus containing SUFU was observed in 21% of tumours, accompanied by disordered expression of Hedgehog pathway genes. SUFU depletion was reproducibly associated with reduced transcription of T-cell and macrophage regulators, and increased transcription of the immune checkpoint inhibitor VISTA. In half of all MPM, CDKN2A deletions were accompanied by loss of Interferon Type I genes. The presence of dysregulated Hedgehog immune transcription and loss of Type I Interferons indicate novel approaches to immunotherapy. Introduction The pleura consist of single layers of mesothelial cells that line the surface of the lungs and the adjacent chest wall. Once inhaled, insoluble asbestos fibres encourage inflammation and fibrosis, normally adaptive responses that seal off foci of injury. Within mesothelial cells however, fibres induce reactive oxygen species and double strand DNA breakages3 . The latency of 20 to 50 years between asbestos exposure and disease means that MPM incidence is peaking in western societies that banned asbestos during the late 20th century. MPM causes 2,500 UK deaths a year and there will be a further 50-60,000 estimated cases by 2050. Global mesothelioma deaths are estimated to be 38,400 each year4 . MPM is classified histologically into epithelioid, biphasic (mixed) and sarcomatoid subtypes. Epithelioid histology accounts for most cases and has a slightly better prognosis5 . MPM grow remorselessly within the thoracic cavity, with metastasis usually late and uncommon. Intense accompanying fibrosis is a major cause of pain and dyspnoea. Previous genomic analyses of MPM have shown a mutational landscape dominated by loss of function mutations in BAP1 and NF26,7 . Larger structural variations in MPM are common8 , and recurrent