Increased expression of the ABCB1 protein, which is known to induce resistance to Adriamycin (doxorubicin) and Abraxane (paclitaxel) in ovarian cancer patients, may also cause resistance to other ovarian cancer treatments.
The study, “ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells,” published in the British Journal of Cancer, suggests that some second-line chemotherapies should be avoided in patients who have already developed resistance to first-line therapies with taxanes.
“Drug resistance is a major complication for many ovarian cancer patients,” Dr. Gillian Smith, who led the research at the University of Dundee in Scotland, said in a press release. “Our study shows an important resistance mechanism which is common to drugs used routinely in the clinic and to new drugs which are being tested in clinical trials.”
Standard of care for patients with ovarian cancer often includes a first-line combination of Paraplatin (carboplatin) and Abraxane, but some cancers develop a resistance and stop responding to those therapies. One possible mechanism that allows the cells to acquire resistance is the upregulation of ABCB1, which pumps the drugs out of the cancer cells.
In women with BRCA mutations, a new family of drugs called PARP inhibitors has been showing promising results in clinical trials in patients who progressed or failed to respond to taxane-based therapies. However, researchers found the ovarian cancer cells which became resistant to certain PARP inhibitors, including Lynparza (olaparib) and drug candidate rucaparib, also used ABCB1 to survive treatment.
“This research increases our understanding of how drug resistance develops in ovarian cancer at a cellular level,” said Nell Barrie, senior science information manager at Cancer Research UK. “It shows for the first time that the same mechanism that causes ovarian cancer to become resistant to paclitaxel also applies to some PARP inhibitors and other chemotherapy treatments.”
These findings are important because ABCB1 expression in ovarian cancer may be used to predict and monitor the onset of drug-resistant disease in each patient, as well as to provide information on the most rational drugs that should be used in second-line therapies.
“Increasing our understanding of resistance mechanisms will allow us to develop tests to spot drug resistance more easily and to make sure patients are given the most appropriate drugs,” said Smith. “Understanding the biology of drug resistant cancers could also lead to the development of new treatments that block cancer’s escape, making them susceptible to therapy again.”
Importantly, the researchers found that ABCA1 expression in ovarian cancer cells did not result in resistance to other PARP inhibitors, called veliparib and AZD2461. This means that such investigational drugs may be suitable to treat patients who are resistant to Abraxane or Adriamycin.