Cancer Cells Resist Targeted Treatment: UK Researchers

PARP inhibitors, an acronym for poly adenosine diphosphate-ribose polymerase, an enzyme that repairs the damages caused by the cancer cells in the body, have been the go-to treatment for doctors treating thousands of patients worldwide. But a recent study shows that cancer cells can learn to resist PART inhibitors and dodge their effects.

A study led by scientists at The Institute of Cancer Research, London, also believes that several existing drugs can improve the efficacy of the inhibitors by stopping the cancer cells from removing the PARP enzymes.

Professor Chris Lord and his team at The Institute of Cancer Research (ICR) have found out that the olaparib and rucaparib, two PARP inhibitors used mainly to treat ovarian, breast, prostate, and pancreatic cancers.

PARP inhibitors usually target PARP1 proteins that help the DNA to repair itself and lock it in its place to stop its action. If the DNA cannot repair itself, it will die, causing the elimination of the cancer cell.

Lord said, "PARP inhibitors are one of the most exciting classes of precision medicine in cancer treatment today, but we are only now gaining a fuller understanding of why they work in some patients but not in others."

The researchers tried to find out proteins that attached themselves to the PARP1 when it is trapped, causing it to get detached from the DNA and they found that a molecule called p97 that unlocks the PARP inhibitor and thus saves the cancer cells from destruction. The researchers then discovered that blocking p97 in patients with tripple negative breast cancer has made the cancer cells much more vulnerable to the PARP inhibitors present in Talazoparib. The efficacy rate 1nM dose of the medicine went from 30% to 90% when p97 was blocked.

Lord added, "Now that we have uncovered p97's role in controlling PARP inhibitor resistance, we could, in future offer treatments that could save many more lives. We believe our findings will help us predict which patients should get a PARP inhibitor, which patients might need to combine a PARP inhibitor with other drugs to stand the best chance of successful treatment, or which patients might be better off on a different treatment altogether."

Dr. Simon Vincent, Director of Research, Support and Influencing at Breast Cancer Now, said, PARP inhibitor drugs work well against cancer cells with an altered BRCA gene, however, they don't work for everyone and some cancers become resistant to this targeted treatment, making it important we continue to fund research into understanding drug resistance. Excitingly, this research suggests that a medicine currently used to treat alcohol addiction could be used in combination with PARP inhibitors to make treatment for breast cancer, caused by an altered BRCA gene, more effective."

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