Tumour Hypoxia Induces DNA Repair Vulnerabilities Through ‘Contextual Loss-Of-Heterozygosity’

Intratumoural hypoxia leads to decreased expression in DNA damage response (DDR) and repair pathways. Given the ‘two-hit’ model for loss of gene function, we hypothesize that hypoxia-mediated down-regulation of gene expression and function, coupled with an already inactive allele contributes to an exploitable ‘contextual loss-of- heterozygosity’ phenotype. To interrogate this relationship, isogenic DLD-1 cells heterozygous and homozygous null for BRCA2, were placed under normoxic (21%) or hypoxic (0.2%) conditions for 72 hours. Hypoxia-mediated changes in DDR response and DNA repair were evaluated by cell proliferation, western blots, qPCR, immunofluorescence and clonogenic assays. Herein, we demonstrate a mechanism of ‘contextual loss-of heterozygosity’, which marries the tumour microenvironment and innate genetic alterations. The resultant increased sensitivity to DDR kinase inhibitors and PARPi highlights the therapeutic significance of this phenomenon and potential clinical utility.M.Sc