GROUNDBREAKING RESEARCH Breakthrough in breast cancer drug resistance
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Researchers led by Professor Alan Ashworth at the Breakthrough Breast Cancer Research Centre have made important steps forward in understanding how cancer cells become resistant to drug treatment.
Breast cancer cells with an inherited genetic defect in the BRCA1 or BRCA2 genes are particularly sensitive to carboplatin, a drug developed many years ago at the ICR, and a new class of anticancer drugs called PARP inhibitors. The use of PARP inhibitors to treat cancers caused by BRCA mutations is a new treatment strategy developed by Professor Ashworth’s team, and which is currently being tested in clinical trials both at the ICR and elsewhere. However, as with most drugs, cells can become resistant to carboplatin or PARP inhibitors. The team discovered that resistance to PARP inhibitors in cells can occur through restoration of the normal function of BRCA2. In the clinic, they also made the important observation that in some ovarian cancers the same mechanism causes relapse in patients on carboplatin.
The team have also searched for ways to detect which patients might respond to treatment with PARP inhibitors. Using a screening approach they identified some members of a class of proteins called kinases that can affect sensitivity to these drugs. The identified kinases may prove to be valuable "biomarkers" that could indicate patients who would benefi t the most from treatment. Professor Ashworth and colleague Dr. Christopher Lord have also studied patient resistance to the anti-oestrogen drug tamoxifen. This resistance is an important cause of breast cancer recurrence. They discovered that tamoxifen resistance was associated with low levels of a kinase enzyme called CDK10. Patients with low levels of CDK10 in their tumors are less likely to benefit from tamoxifen treatment. This has important implications for women with breast cancer.
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