The new approach allowed observation of the effect of specific mutations on PARP1 and on the sensitivity of cancer cells to PARP inhibitors. Credit: The Institute of Cancer Research.

Researchers at the Institute of Cancer Research (ICR) have discovered a mutation that causes tumour cells to become resistant to breakthrough cancer treatment olaparib and other poly (ADP-ribose) polymerase (PARP) inhibitors.

The research team used CRIPSR-Cas9 gene editing to identify a specific mutation in the PARP1 protein involved in DNA repair that is a target for PARP inhibitors.

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They created mutations in the PARP1 gene and tagged this altered protein with a fluorescent protein to track its effects on cancer cells’ sensitivity to the PARP drugs.

The team was able to pin-point specific PARP1 mutations that stop protein binding to DNA and hinder the drugs’ mechanism of action.

They observed that certain tumour cells can withstand the loss of the DNA repair function, thus becoming resistant.

This discovery could help identify patients who may develop resistance to the PARP inhibitors, enabling doctors to decide further treatment plans early.

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“Testing for the mutations we have identified could offer even more personalised treatment for women with breast and ovarian cancer.”

While additional research is required to confirm these findings, testing for this mutation could improve the personalisation of an already targeted treatment.

ICR Breast Cancer Now Research Centre, cancer genomics staff scientist Dr Stephen Pettitt said: “PARP inhibitors are hugely exciting new drugs which are especially effective in women with BRCA mutations, but unfortunately as with many other treatments it is common for cancer cells to eventually develop resistance.

“Our study has discovered one of the reasons why resistance to PARP inhibitors such as olaparib might occur.

“Testing for the mutations we have identified could offer even more personalised treatment for women with breast and ovarian cancer, by allowing doctors to judge whether and for how long olaparib should be used.”

Researchers are planning to apply this gene-editing technique to resistance to other drugs, and potentially predict the speed at which resistance progresses.