ATR inhibitors prove effective in two pre-clinical models of cancer

September 13, 2016, Centro Nacional de Investigaciones Oncológicas (CNIO)
The image shows the effect of treatment with ATR inhibitors in an acute myeloid leukaemia model. On the left , animals with leukaemia that has spread throughout the body. On the right, the effect of treatment. Credit: CNIO

Tumours are an accumulation of cells that divide without control, accumulating hundreds of chromosomal alterations and mutations in their DNA. These alterations are triggered in part by a type of damage to the DNA known as replicative stress. To survive in the face of this chaos, tumour cells need the intervention of the damage response protein ATR, known for its role as guardian of genome integrity, to which they become addicted. After eight years of work, Oscar Fernández-Capetillo's team at the Spanish National Cancer Research Centre (CNIO) has discovered that blocking this protein has antitumour effects in several animal models of cancer, such as an aggressive type of acute myeloid leukaemia and Ewing sarcoma. The results were presented in two papers published in Science Signaling and Oncotarget.

The work performed by Fernández-Capetillo's team was premised on the assumption that if tumours suffer from high levels of replicative stress, they could be particularly sensitive to treatments with drugs that inhibit ATR, since this protein is responsible for reducing this type of stress. In addition, as healthy cells hardly suffer from this type of stress, the effects on those cells would be limited. The researcher explains it as follows: "If you eliminate a fireman [ATR] in a town where there is no fire [healthy cells] nothing happens, but if you do the same in a town where there is a fire [ with greater damage to their DNA than ], the fire will spread and destroy the town".

Attack the guardian

In 2011, Fernández-Capetillo's team proved that it was on the right track. In two independent papers published in the prestigious journal Nature Structural & Molecular Biology they reported, for the first time, that blocking ATR was particularly toxic to tumour cells; a conclusion they reached by using cell cultures and genetic mouse models.

Having made this conceptual breakthrough, "the next step was to focus on finding tumours that presented the greatest replicative stress levels, because we believe that these are the type that will benefit most from this new therapy", says Fernández-Capetillo.

According to data published by the laboratory itself, tumours with high replicative stress levels tend to have high levels of CHK1 protein -also involved in suppressing replicative stress- to survive in these adverse conditions. "This suggested that one way of identifying tumours with high levels of replicative stress was simply to determine how much CHK1 was present", explains Fernández-Capetillo. Consequently, after analysing CHK1 levels in a broad panel of human tumours, the researchers identified two types with very large quantities of this protein: Ewing sarcoma and several types of lymphoma and leukaemia, including acute myeloid leukaemia.

Improved survival and effectiveness

In the case of , they focused on tumours with mutations affecting the MLL gene, a subtype with a poor prognosis and for which there is currently no curative treatment. Using mouse models that recapitulates this specific type of leukaemia, the researchers observed how the ATR inhibitors increased the survival expectancy of the mice by up to six times. "This is the first time we have seen an effect of such magnitude. To date, using these animal models, we had not seen any compound that achieved this degree of response", the authors explain. "One difference with current chemotherapy is that ATR inhibitors induce cell death regardless of the presence of p53; therefore, it is also effective in tumours that lack this gene. In addition, we should that treatments involving ATR inhibitors were based solely on the use of these compounds, without any additional combination involving other drugs".

In the case of Ewing sarcoma, ATR inhibitors showed a very high toxicity level, both on culture plates as in the animal models with tumour grafts. "The response observed is better than that reported for other agents that are currently undergoing clinical testing, suggesting that these compounds are an alternative for the future".

Explore further: Scientists discover a new mechanism of resistance to chemotherapy

More information: I. Morgado-Palacin et al, Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML, Science Signaling (2016). DOI: 10.1126/scisignal.aad8243

Related Stories

Scientists discover a new mechanism of resistance to chemotherapy

April 7, 2016
The occurrence of chemotherapy resistance is one of the major reasons for failure in cancer treatment. A study led by Óscar Fernández-Capetillo, Head of the Genomic Instability Group at the Spanish National Cancer Research ...

Gene known to protect against cancer can also promote tumor growth: study

March 13, 2012
Can a gene simultaneously protect against cancer and favor its growth? Researchers at the Spanish National Cancer Research Centre have discovered a gene with this double-edged property and suspect there may be many more that ...

A new mechanism that contributes to the evolution of cancer

January 31, 2013
Cancer arises from the accumulation of mutations and structural changes in chromosomes, which in some cases give rise to combinations that favour the growth or expansion of the disease. In this context, chromosomes tend to ...

'Cell' article reveals new resistance mechanism to chemotherapy in breast and ovarian cancer

June 18, 2013
It is estimated that between 5% and 10% of breast and ovarian cancers are familial in origin, which is to say that these tumours are attributable to inherited mutations from the parents in genes such as BRCA1 or BRCA2. In ...

Researchers propose a new combined therapy to treat cancer

February 6, 2014
A large part of the effort dedicated to cancer research is directed towards the search for combinations of existing drugs—many of which have already been introduced into clinical practice—that permit higher overall survival ...

Recommended for you

Healthy diets linked to better outcomes in colorectal cancer

October 20, 2018
Colorectal cancer patients who followed healthy diets had a lower risk of death from colorectal cancer and all causes, even those who improved their diets after being diagnosed, according to a new American Cancer Society ...

Scientists to improve cancer treatment effectiveness

October 19, 2018
Together with researchers from the University of Nantes and the University of Reims Champagne-Ardenne in France, experts from the National Research Nuclear University MEPhI have recently developed a quantum dot-based microarray ...

Why some cancers affect only young women

October 19, 2018
Among several forms of pancreatic cancer, one of them specifically affects women, often young. How is this possible, even though the pancreas is an organ with little exposure to sex hormones? This pancreatic cancer, known ...

Mutant cells colonize our tissues over our lifetime

October 18, 2018
By the time we reach middle age, more than half of the oesophagus in healthy people has been taken over by cells carrying mutations in cancer genes, scientists have uncovered. By studying normal oesophagus tissue, scientists ...

Study involving hundreds of patient samples may reveal new treatment options of leukemia

October 17, 2018
After more than five years and 672 patient samples, an OHSU research team has published the largest cancer dataset of its kind for a form of leukemia. The study, "Functional Genomic Landscape of Acute Myeloid Leukemia", published ...

A 150-year-old drug might improve radiation therapy for cancer

October 17, 2018
A drug first identified 150 years ago and used as a smooth-muscle relaxant might make tumors more sensitive to radiation therapy, according to a recent study led by researchers at The Ohio State University Comprehensive Cancer ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.