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Understanding cancer cell dependency on ATR/ATM: a Metabolism or DNA repair tale?
Closing date
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Supervisors
Dr Katiuscia Bianchi, k.bianchi@qmul.ac.uk, My research aims to reveal how cancer cells evolve to proliferate and evade cell death in order to develop new therapeutic strategies, in particular for the treatment of breast cancer., Queen Mary University of London
Prof Gyorgy Szabadkai, g.szabadkai@ucl.ac.uk, The overarching aim of my research group is to understand how transcriptional and translational regulation of the mitochondrial proteome (termed as mitochondrial biogenesis) is converted into bioenergetic and signaling responses of the organelle. , University College London
Project Details

Importance

Drug resistance is a major limiting factor to cure a wide range of diseases. Similarities in drug resistance mechanisms can be found in apparently very distant disorders, such as cancer and infectious diseases. Accordingly, one solution to combat drug resistance in cancer, i.e. the combination of different agents with non-overlapping mechanism of actions, was taken from the rulebook of antimicrobial therapy1. Here we will investigate how DNA damage repair targeting drug resistance mechanisms can be driven by metabolic cues, which will generate potential actions to overcome drug resistance in many diseases.

Rationale

Cells are constantly exposed to DNA-damaging agents, thus they developed a complex DNA damage response (DDR) to maintain genomic stability and survive. Key players of DDR are Ataxia telangiectasia and RAD3-related (ATR) and Ataxia telangiectasia mutated (ATM) kinases, which therefore are attractive targets for cancer therapy.

ATR inhibitors (in clinical trials) have demonstrated a dose-dependent tumour growth inhibition when used as monotherapy mainly in ATM-deficient xenograft models, suggesting a role for ATM in inducing drug resistance2. While this ascertains that in patients with ATM loss/mutations the drug is more effective, on the other side it also represents a major limitation to its utilization. Thus, understanding how ATM mediates resistance to an ATR inhibitor is of major interest. ATM is also known as a major regulator of cellular metabolism, thus we will test the hypothesis that mitochondrial and metabolic changes linked to ATM deficiency lead to drug resistance. The expected outcome is to understand how changes in cellular metabolism may lead to drug resistance and identify new pharmaceutical routes to modulate cell sensitivity to chemotherapeutic drugs.

Methodology:

The student will have access to cutting technologies to develop this project: (i) the MS facility for metabolic flux analysis of the Barts School of Medicine and Dentistry, (ii) the Core Facility for Metabolic and Mitochondrial Studies of UCL and (iii) the DNA damage response unit in AstraZeneca.

Lab based work will be combined with bioinformatics to study the mitochondrial profile and metabolic fluxes of cells with ATM deficiency.

References

1.         Vasan, N. Nature 575, 299–309 (2019).

2.         Reaper, P. M. Nat. Chem. Biol. 7, 428–430 (2011).

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