Pharmacological targeting of chromosome 9p21 deletion for effective therapy of malignant pleural mesothelioma.

Malignant mesothelioma is an aggressive tumour with a dismal prognosis, inadequate therapy choices, and no cure at this time. The chromosome 9p21 (ch9p21) locus encodes the tumour suppressor CDKN2A gene and MTAP gene. Ch9p21 is one of the most common somatic alterations in mesothelioma, and it is associated with shorter patient survival. MTAP deletion has been shown to inhibit methionine-dependent protein arginine methyltransferase 5 (PRMT5), an epigenetic regulator, through the accumulation of its substrate methylthioadenosine (MTA). PRMT5 has been reported to be a vulnerability in MTAP deleted tumours.

The aims of the PhD project are to understand how ch9p21 clonal architecture impacts prognosis and determine whether ch9p21 could be viable for therapy.

Results revealed that MTAP protein deficiency in mesothelioma, accurately predicts ch9p21 clonal deletion. Ch9p21 loss and MTAP/CDKN2A co-deletion are predominantly clonal events that are associated with a shorter progression free survival (PFS). Additionally, I discovered an association between shorter median overall survival (OS)/PFS and the deletion size of ch9p21 for the first time in mesothelioma patients. Methionine depletion using Methionine-gamma-lyase (MGL) is effective on mesothelioma cells and live mesothelioma explants, and MTAP deletion does not sensitise MGL response in mesothelioma cells. MGL induces senescence in mesothelioma cell lines, and further investigation is required for this novel effect. Finally, MTAP/CDKN2A co-deletion enhances the efficacy of abemaciclib therapy, and the increase in ch9p21 loss length increases sensitivity to CDK4/6-inhibition in mesothelioma patients. Ch9p21 loss is therefore predictive for CDK4/6 inhibition and may facilitate stratification of therapy in mesothelioma.