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Novel cause of ovarian cancer drug resistance identified

Panos Konstantinopoulos, MD, PhD - largePanos Konstantinopoulos, MD, PhD

Dana-Farber Cancer Institute scientists have shed new light on why some ovarian cancers don’t respond to or learn to evade standard chemotherapy and targeted drugs. They say the discovery could aid in developing strategies to combat ovarian drug resistance.

The investigators’ research, posted online by the journal Cell Reports, identified a previously unknown resistance culprit – a tiny piece of genetic material called a microRNA, or miRNA – that the cancer cells use to regain their DNA repair powers.

The study focused on the 15 to 20 percent of epithelial ovarian cancers harboring inherited BRCA1 and BRCA2 mutations. Because such tumors can’t repair damage to their DNA effectively, are vulnerable to platinum-based chemotherapy agents and newer targeted drugs called PARP inhibitors that shred the tumors’ DNA molecules.

While these drugs are often effective, a substantial number of patients don’t respond to them or become resistant to the drugs, reducing their long-term survival. One way that BRCA1 and 2 -mutant ovarian tumors outwit treatment is by gaining additional mutations that restore their molecular DNA-repair pathways.

In the new research, however, senior authors Dipanjan Chowdhury, PhD and Panos Konstantinopoulos, MD, PhD of Dana-Farber Cancer Institute discovered a different resistance mechanism that that doesn’t involve acquiring new mutations. Instead, the ovarian cancer cells turn off one of two competing DNA repair pathways and turn on another pathway, known as homologous recombination (HR) that enables the tumor to resist platinum drugs and PARP inhibitors. This repair pathway switch occurs in cancer cells that make increased levels of a specific micro-RNA, miR-622, which turns out to be a regulator of DNA repair.

Dipanjan Chowdhury, PhD - largeDipanjan Chowdhury, PhD

The scientists found that laboratory-grown cancer cells overexpressing miR-622 were resistant to the PARP inhibitors olaparib and veliparib, and also to chemotherapy agents carboplatin and cisplatin. Next, they looked for an association between increased levels of miR-622 and outcomes of ovarian cancer patients represented in a database compiled by The Cancer Genome Atlas project (TGCA). They examined data from 89 patients with BRCA1-mutated ovarian cancer who had undergone surgery followed by treatment with platinum-based chemotherapy.

“In all cases,” the researchers note, “we consistently found that tumors with higher miR-622 expression were associated with inferior response to first-line platinum-based chemotherapy and worse survival.” Patient with higher expression of miR-622 survived a median of 39 months compared with 49.3 months for patients with lower levels of miR-622.

Micro RNAs are very small genetic units that are not blueprints for making proteins. Instead, they’re believed to belong to an ancient system for regulating genes in plants and animals. The human genome contains an estimated 2,500 miRNAs, whose importance only became clear beginning in the early 2000s. Abnormal miRNA activity has been linked to a number of diseases including cancers such as leukemia, lymphoma, and solid tumors.

Dana-Farber investigators showed that overexpression of miR-622 suppresses the production of two proteins, Ku70 and Ku80, which play an important role in determining which of the two DNA repair pathways is dominant.

As a result of their discovery, it’s possible that measuring levels of miR-622 in BRCA1-mutant ovarian cancer could help guide treatment of the tumors. Moreover, “miR-622 may be a promising target for augmenting response to PARP inhibitors and platinum chemotherapy for these tumors,” according to the researchers.

Konstantinopoulos is a medical oncologist in the Susan F. Smith Center for Women’s Cancers at Dana-Farber, and Chowdhury is in the department of radiation oncology at Dana-Farber.

First author is Young Eun Choi is a postdoctoral fellow in the Chowdhury laboratory. Funding for study comes from Department of Defense Ovarian Cancer Academy Award W81XWH-10-1-0585, NCI grant R01CA142698-07 and the Deborah and Robert First Foundation.

9/22/2017 9:56:35 PM
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