Changes in Gene Copy Number Sensitize Ovarian Cancer Cells to FDA-Approved Drugs, Study Finds

Changes in Gene Copy Number Sensitize Ovarian Cancer Cells to FDA-Approved Drugs, Study Finds

Gaining or losing a copy of a gene — a characteristic of cancer cells — disrupts specific signaling pathways and leads to cancer progression.

Researchers studying these genetic alterations in ovarian cancer cells have found that a pathway involved in  autophagy —  a physiological process that deals with the destruction of cells — was the most affected by copy-number alterations. But a combination of approved drugs proved effective in eliminating ovarian cancer cells, including those that resisted standard chemotherapy.

The study, “Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer,” appeared in Nature Communications.

“When most people think about cancer genetics, they think about single key mutations that foster tumor formation —very specific things like the BRCA genes,” the paper’s lead author, Joe R. Delaney, PhD, said in a news release. “These changes are often referred to as tumor drivers but these are not the only deviations that impact cancer growth. We explored other possibilities.”

The loss or gain of a single copy gene accounts for more than 90 percent of all genetic changes in cancer cells. Instead of the normal two copies of a gene — one from the mother and one from the father — cancer cells might have only one copy or three copies of a single gene. But researchers often look at particular gene mutations rather than copy-number alterations, leaving this area largely unexplored.

The team led by Delaney — a fellow at the University of California-San Diego Moores Cancer Center — developed a computational tool, called Haploinsufficient/Triplosensitive Gene (HAPTRIG) to understand whether certain cancers had copy-number alterations in genes associated with specific pathways.

They found that more that 60 percent of genes were affected, and that the autophagy pathway was particularly disrupted by such alterations.

Autophagy is a natural process by which the cells get rid of faulty or toxic components, allowing them to maintain their normal health. Ovarian cancer cells use this process very frequently, but the researchers found that they also lose several copies of autophagy genes, resulting in a compromised pathway.

This led the researchers to hypothesize that autophagy-stressing drugs that further disrupted the pathway could induce tumor cell death. Using drugs that targeted autophagy and that are approved by the U.S. Food and Drug Administration, the team found several mouse models of ovarian cancer, including those that were resistant to standard chemotherapy, to be highly sensitive to the treatment.

Importantly, the combination of drugs tested was relatively cheap and less toxic than standard treatments.

Dwayne G. Stupack, PhD, the study’s senior author and an associate professor at Moores Cancer Center, suggests that the drug combo should be clinically evaluated.

“Our study suggests that a roadmap of targetable genetic changes in tumors should not be limited to mutations,” said Stupack. “HAPTRIG may reveal additional targetable pathways across cancer types. We have provided a free web tool to allow the community to easily perform a HAPTRIG analysis on 21 cancer types.”

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Inês Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.

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