Small genetic script causes drug resistance in some ovarian cancers

Scientists from Dana-Farber Cancer Institute have identified a tiny piece of genetic code in certain ovarian tumors that allows them to resist treatment with platinum chemotherapy and PARP inhibitor drugs.

The short genetic script, a microRNA or miRNA, alters several molecular pathways in the cells of ovarian tumors harboring a BRCA2 mutation that restores the cancer cells’ ability to repair damage causes by the drug treatments, say Dana-Farber investigators.

The resistance mechanism caused by a particular microRNA called miR-493-5p occurred only in BRCA2-mutant ovarian cancers, and not those cancers containing a BRCA1 mutation, according to the study in Cell Reports.

The finding could open new approaches to attacking these resistant ovarian cancers, as well as other types of tumors, say the researchers, led by Panagiotis Konstantinopoulos, MD, PhD, and Dipanjan Chowdhury, PhD.

MiRNAs are a family of small pieces of the genetic material RNA that don’t carry the code to make a protein. They regulate a wide range of biological processes and have been found to be frequently abnormally regulated in cancer cells.

The study showed that women with ovarian cancer who carried a mutated BRCA2 genes, and who also had high activity of miR-493-5p in their cancer cells, had much worse survival following platinum chemotherapy treatment than did those whose cells had low activity of the microRNA – the difference reflecting the development of drug resistance caused by miR-493-5p.

“This shows the power that a small piece of genetic code expressed in a tumor can have,” said Chowdhury.

High-grade serous ovarian cancers whose cells carry mutated BRCA1 or BRCA2 genes have a defect in their ability to repair a certain kind of DNA damage; as a result, they are sensitive to platinum-based drugs and PARP inhibitors. Drugs in the PARP inhibitor category include olaparib, rucaparib, and niraparib.  However, many of these cancers eventually become resistant to these treatments, and patients relapse. Often, this occurs because a second mutation occurs in the BRCA1 or BRCA2 gene, and that mutation restores the cancer cells’ ability to repair DNA damage through what is known as homologous recombination repair, or HRR.

However, the Dana-Farber investigators were looking for other mechanisms that could cause drug resistance in ovarian tumors with BRCA1/2 mutations. Because they had previously identified an miRNA as a cause of resistance in BRCA1-mutant ovarian cancers, they focused their search on other miRNAs. They sequenced miRNAs extracted from 38 primary and recurrent ovarian tumors, and included some that were sensitive to platinum drugs and others that were resistant. 

Studying this group of tumor samples, along with a larger dataset from The Cancer Genome Atlas collection of tumors, the researchers found that miR-493-5p was linked to the development of platinum and PARP inhibitor drug resistance – but only in tumors with BRCA2 mutations.

The next question was, how was this tiny bit of RNA – measuring only 22 base pairs, or letters of the genetic code, in length – restoring ovarian cancer cells’ ability to repair damage? Further experiments revealed that miR-493-5p targets several genes involved in keeping the cancer cells’ genome stable – that is, preventing the cells from being fatally affected by treatment with platinum or PARP inhibitor drugs.

The importance of this findings is twofold, say the investigators. It will be possible to test patients’ ovarian tumors for activity of miR-493-5p, and if it is found to be highly active, that could suggest platinum and PARP inhibitor drugs would not be the best choice for treatment.

Farther in the future, the scientists say developing drugs that block the action of miR-493-5p may be a strategy for re-sensitizing ovarian tumors to the damaging effects of platinum chemotherapy and PARP inhibitors.

The research was supported by National Cancer Institute grants R01CA208244 and R01CA142698=07, and Department of Defense grant W81XWh-15-0564/OC140632.