Research published on 11 March by scientists at Kent and The Institute of Cancer Research, London, reveals a potential new approach to cancer treatment.
The study, published in the journal Cancer Research, shows that blocking the action of proteins that help to duplicate a cancer cell’s DNA can increase the activity of a new class of cancer drugs known as CHK1 inhibitors.
CHK1 is a key protein within a cell, responsible for how it repairs itself when damaged. Cancer cells damaged from treatments such as chemotherapy may need the CHK1 protein to repair and survive, making it a target for researchers in the fight against cancer.
The current study used the drug SRA737, a CHK1 inhibitor identified on a research project initiated by Professor Michelle Garrett, formerly of The Institute of Cancer Research (ICR) and now Professor of Cancer Therapeutics at the University of Kent’s School of Biosciences. The cancer cell killing activity of SRA737 was enhanced by blocking the function of the B-family of DNA polymerases that are important for DNA replication. This was achieved in both lung and bowel cancer cells using an experimental inhibitor of B-family DNA polymerases combined with SRA737.
The study also reports that cancer cells with low amounts of B-family polymerases may also be more susceptible to treatment with CHK1 inhibitors alone. This potentially provides a way to identify those cancer patients who may respond to a CHK1 inhibitor such as SRA737.
Of the discovery, Professor Garrett said: ‘This work shows the potential benefit of blocking B-family DNA polymerases to boost the activity of drugs like SRA737 that target CHK1. It’s important too we have shown that detection of low levels of B-family DNA polymerases in tumours could be used to identify patients most likely to respond to a CHK1 inhibitor. Both discoveries offer a new approach to cancer treatment.’
Study co-leader Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said: ‘Our new study establishes the basis for a potentially exciting new approach to treatment involving a two-pronged attack on cancer. We found that doubling up on drugs that target the systems for repairing DNA could be effective even against cancers that do not respond to single-drug treatment. Our findings also provide us with a way of picking out which patients are most likely to benefit from existing CHK1 inhibitors like SRA737 – a highly innovative drug discovered at the ICR and currently in clinical development.’
The paper ‘CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells’ is published in the journal Cancer Research.
Authors: Rebecca F. Rogers (1), Mike I. Walton (1), Daniel L. Cherry (2), Ian Collins (1), Paul A. Clarke (1), Michelle D. Garrett (2) and Paul Workman (1).
1 – Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK
2 – School of Biosciences, Stacey Building, University of Kent, Canterbury, Kent, CT2 7NJ, UK
To read the paper, please follow: https://cancerres.aacrjournals.org/
DOI number: 10.1158/008-5472.CAN-19-1372