Potentiation of cancer therapy by novel pharmacological inhibitors of DNA repair

There is evidence that DNA-dependent protein kinase (DNA-PK) and Ataxia Telangiectasia Mutated (ATM) genes modulate response to DNA-interactive agents such as cisplatin and impact on DNA repair following chemotherapy. Recent studies have shown DNA-PK/ATM involvement in immunological response, MEK activation and response to chemotherapy. Whilst intra-tumour heterogeneity (ITH) is considered one of the main reasons for failure of targeted therapeutics, mutational burden associated with ITH may promote generation and presentation of tumour neo-antigens to the immune system. We hypothesize that agents promoting DNA damage and prevent DNA repair will significantly increase the mutational burden of cancerous cells thus increasing immunogenicity. With the development of specific and potent DNA-PK and ATM inhibitors, we will address optimization of chemotherapeutic effects. We will examine effects of DNA-PK/ATM inhibition on cisplatin-induced DNA damage/repair in cellular models and patient-derived xenografts. Additionally we will assess the impact of these agents on immunogenicity using exome and RNAseq to assess mutational burden of cancer models cultured in presence/absence of the novel inhibitor.