Compensating for loss of neurodegenerative disease gene ATM offers insights into cancer drug resistance.
Scientists at the University of Cambridge have identified mechanisms by which drug sensitivities characteristic of ATM-deficient cells can be counteracted by changes in other genes. These results are important for both understanding cancer drug resistance in the context of sporadic cancers, as well as highlighting potential therapeutic targets for the genetic disease, ataxia-telangiectasia.
Mutations in the ATM gene cause the devastating neurodegenerative and cancer predisposition disease called ataxia-telangiectasia (A-T), and are also associated with various forms of sporadic cancer.
Previous work has shown that the ATM protein, which is produced from the ATM gene, serves as a “molecular guardian of the genome” by detecting DNA damage and promoting its repair. Consequently, A-T patients and ATM-deficient cells are hyper-sensitive to various endogenous DNA lesions that can lead to neurodegeneration, as well as DNA-damaging agents used in cancer therapy such as PARP inhibitors.
As described by their publication in Nature Communications (DOI: 10.1038/s41467-018-07729-2), researchers in the laboratory of Professor Steve Jackson at The Gurdon Institute, University of Cambridge, have collaborated with colleagues at AstraZeneca to identify mechanisms by which the drug sensitivities of ATM-deficient cells can be alleviated by changes in other genes. Thus, through using cutting-edge CRISPR-Cas9 genetic screens, the authors show that defects in the products of several genes also involved in DNA repair pathways, including components of the BRCA1-A complex and the non-homologous end joining factors LIG4, XRCC4 and XLF, can alleviate the hypersensitivity of ATM-deficient cells to PARP inhibitors and the chemotherapeutic drug topotecan.
In addition to this work providing new mechanistic insights into how cells respond to DNA damage, these findings also have potential medical relevance. First, they suggest how cancers with ATM mutations might evolve resistance in the clinic and how this may make these resistant cancers susceptible to other anti-cancer agents. Second, they suggest potential therapeutic targets for A-T.
Dr. Gabriel Balmus from Dementia Research Institute at University of Cambridge, and Domenic Pilger, Jackson lab Cancer Research UK graduate student, who are co-lead authors on the paper said “We are excited by the publication of our research and by the possibility that it might improve cancer therapies and could lead to a therapeutic approach for the neurodegenerative disease A-T.”
Dr. Josep Forment, Oncology Team Leader at AstraZeneca who is co-lead and co-corresponding author of the study said “It has been wonderful collaborating with the group of Prof Steve Jackson to carry out these exciting studies. My colleagues and I at AstraZeneca are now exploring how these findings might lead to the discovery of more effective cancer treatments.”
Prof Steve Jackson commented "This study marks a major step forward in our understanding of how the ATM protein maintains genome stability and how ATM defects can cause cancer and neurodegeneration in human patients with A-T. My colleagues and I are very excited by the potential clinical applications for our findings, which we now plan to actively pursue in my laboratory and with our colleagues elsewhere."
ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
Balmus G et al. Nature Communications (08 January 2019)
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About the Wellcome Trust/ Cancer Research UK Gurdon Institute
Named after its co-founder, Nobel Laureate Sir John Gurdon, the Gurdon Institute (part of the University of Cambridge) is a world-leading centre for research into the biology of development and how normal growth and maintenance go wrong in diseases such as cancer.
More than 240 scientists work in the Gurdon Institute’s purpose-built laboratories on projects ranging from breast cancer and brain development to liver regeneration and leukaemia. Many have made pioneering contributions to the fields of basic cell biology, cellular reprogramming, epigenetics and DNA repair.
Institute scientists use a range of model systems such as yeast, nematode worms, fruit flies, frogs, mammalian cells and organoids to study development and disease at the level of molecules, cells and tissues.
Research conducted at the Institute has so far led to eleven spin-out companies (including KuDOS Pharmaceuticals, Abcam, Chroma Therapeutics, CellCentric, Gen2Neuro and Adrestia Therapeutics) and five candidate drugs. One of these, the PARP inhibitor olaparib (Lynparza), has been approved in the UK, Europe and the USA for use against ovarian cancers, and in January 2018 in the USA for breast cancers.