Exploring Synthetic Genetic Interactions between FANCD2 Mutations, Mre11 and ATM Inhibition in Fanconi Anaemia

Abstract

At lower concentrations, double inhibition of the ATM and Mre11 pathways with KU55933 and Mirin respectively, was more effective than single inhibition with either of the drugs leading to cell death in FANCD2-/- FA cells. It is critical to investigate further with this combination in various cells and preclinical trials as prospective therapy in FA cells and associated cancer cases.

HIGHLIGHTS • FANCD2-/- (PD20) cells displayed decreased sensitivity to mitomycin C (MMC), indicating the MMC assay was not effective. • Inhibiting the Mre11 pathway using Mirin led to accelerated cell death in FANCD2-/- cells. However, there was no difference in the response of FANCD2-/- cells from the control. • KU55933, an ATM inhibitor, proved lethal to FANCD2-deficient cells, suggesting its potential as a therapeutic agent in Fanconi Anaemia. • Combining Mirin and KU55933 resulted in a cooperative lethal effect on FANCD2-deficient cells at a lower concentration, offering a promising avenue for targeted therapies in Fanconi Anaemia.