Researchers identify method for making resistant kidney cancer treatable again

New research has identified the molecular mechanism that causes kidney cancer to become resistant to drug treatment and could offer a way to reverse the process. The findings, published in the journal Nature Communications, are the work of scientists from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and the US Department of Veterans Affairs.

When cells are functioning normally, nutrients are typically broken down and processed within the mitochondria to make energy available to the body in the form of adenosine triphosphate (ATP).

In 1931, Nobel Prize Winner Otto H. Warburg first observed that ATP switches from within the mitochondria to outside the mitochondria in cancer cells, which makes the cancer cells resistant to drug therapy. Since that time, scientists have been trying to target the critical players so that smart targeting of that pathway could render cancer cells sensitive to drug treatment.

In this study, principal investigator Karen Block, PhD, conducted preclinical experiments and studies in animal xenograft models of human kidney cancer to shed light on the processes.

Building on a groundbreaking 2009 study, Dr. Block and colleagues discovered the presence of an enzyme, NOX4, within the cell’s mitochondria. NOX4 was identified as a culprit in kidney cancer evolution. In this new study, the researchers focused on uncovering the key mechanisms involved.

“In the first study, we learned that the NOX4 enzyme generates oxygen radicals that paradoxically facilitate survival of kidney cancer cells undergoing drug treatment,” said Dr. Block, an associate professor of nephrology at UT Health who recently joined the Department of Veterans Affairs Office of Research and Development in Washington DC. “However, we found that when we reversed energy production back to the mitochondria, free radical production by NOX4 was shut off, allowing the cancer cells to die when exposed to drug treatment.”

Approximately 30% to 40% of patients who have had surgery to remove kidney cancer eventually die because the disease has spread due to the lack of effective drug therapies and drug resistance, according to Ronald Rodriguez, MD, interim dean of the Joe R. & Teresa Lozano Long School of Medicine and professor of urology at UT Health, and a co-author of the study.

“We learned that NOX4’s role in the mitochondria is to sense the energetic switch that Warburg described in the 1930s,” Dr. Block said. “When ATP production changes from the mitochondria, NOX4 turns on to start drug resistance, allowing the cancer cells to survive. We think that when this mechanism starts, it develops a NOX4 perpetual loop, allowing the cancer to grow and spread. We also think there is the potential that the loop can be reversed. More research needs to be conducted to better understand the mechanism and how we may be able to use drugs to intervene and at which stage.”

The study was funded with a Veterans Administration Merit Award and two National Institutes of Health awards.

To read more about this study, click here.