Phenocopying ATM loss via modulation of cellular metabolism to overcome resistance to the ATR inhibitor
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
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Aim1: Using tracer compounds and unpublished preliminary data form AZ, we will investigate the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
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Aim1: Using tracer compounds and unpublished preliminary data form AZ, we will investigate the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
People |
ORCID iD |
Katiuscia Bianchi (Primary Supervisor) | |
Hannah Rouse (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/T008709/1 | 01/10/2020 | 30/09/2028 | |||
2548307 | Studentship | BB/T008709/1 | 01/10/2021 | 30/09/2025 | Hannah Rouse |