Phenocopying ATM loss via modulation of cellular metabolism to overcome resistance to the ATR inhibitor

Our objectives are (i) to characterise the role of ATM in generating resistance to
ATR inhibitors by investigating the effect of ATM deficiency on cellular metabolism; (ii) to investigate
whether we can recreate the metabolic profile of ATM-deficient cells via targeting cellular metabolism and if
this would sensitize cancer cells to AZ6738, mimicking ATM loss. Understand how ATM contributes to
generate resistance to AZ6738, a drug currently in clinical trials, our proposal is of clear relevance for the
pharmaceutical industry and thus in the remit of BBSRC.
Aim1: Using tracer compounds and unpublished preliminary data form AZ, we will investigate the
mechanisms responsible for the metabolic profile of ATM deficient cells.
Aim2: inhibitors are already available for the majority of metabolic pathways, thus we will take advantage of
this underexploited toolbox to mirror the ATM-deficient metabolic phenotype identified in Aim1 and test if
this will sensitise ATM proficient cells to AZ6738.
Aim3: in the cerebellar cortex of Ataxia-telangiectasia patients (carrying mutations in the ATM gene) a set of
mitochondrial genes is deregulated5. In collaboration with GS (UCL - second supervisor) we will identify
cells with a similar mitochondrial phenotype using publicly available dataset (i.e. CCLE) and will test the
sensitivity to AZ6738 of cells with different mitochondria phenotypes.
Expected outcome: understand how changes in cellular metabolism may lead to drug resistance