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Why chemotherapy doesn’t work for certain cancer patients

Scientists find gene that causes drug resistance in cancer

Researchers at the University of Iowa and Brigham Young University have pinpointed a gene that causes cancer patients to develop resistance to drug therapy.

The discovery is a first step in creating new, effective therapeutic treatments for sufferers of aggressive cancers such as multiple myeloma that respond poorly to treatment.

“There are not a lot of options for cancer patients with diseases such as myeloma,” said BYU biology professor David Bearss, a coauthor on the study published Jan. 14 in the journal Cancer Cell. “Myeloma is not only an extremely painful cancer, but it is also a disease that is resistant to treatment.”

Multiple myeloma is a cancer of plasma cells that exists exclusively in the bone. Over time the cancer cells take over bone marrow and destroy its function. This results in major health problems, including failure of the immune system, loss of kidney function, a drop in red blood cell count and large soft spots or holes that form in bones. These holes lead to painful fractures throughout the body, from the skull to hips to the spine.

Compounding that pain for patients is that myeloma cells quickly become resistant to chemotherapy and other drugs, resulting in a short life expectancy for those diagnosed. Over the last few years lead researchers Fenghuang (Frank) Zhan and Guido Tricot, along with Bearss, have been trying to figure out how the disease develops drug resistance.

For the Cancer Cell study, the team carried out a genomic analysis of the biopsied cells of 19 myeloma patients, taken from different stages of their cancer development. They wanted to see what was happening on the genetic level as the disease progressed.

They found that patients with the most aggressive forms of myeloma, and the patients with the poorest drug response, were those who had a high expression of the gene NEK2. That finding led the team to start going after the gene in the lab to see what would happen.

“Silencing NEK2 in cancer cells potently decreased drug resistance, induced cell-cycle arrest, cell death, and inhibition of cancer cell growth in vitro and in vivo," said Zhan, professor of internal medicine at University of Iowa’s Carver College of Medicine.

Added Bearss: “We were able to show that if we inhibit NEK2, then we can actually restore sensitivity to drugs that we use right now.”

The research results also indicate that NEK2 can be used in diagnostic testing.

“We’ve found that this gene is not just a predictor of poor therapy response in myeloma, but is a predictor to poor response in other cancers, such as breast cancer, lung cancer and other major tumor types,” Bearss said. “A big take home from this study is that we could potentially use NEK2 for early screening of patients so we could treat patients with higher levels more aggressively.”

Bearss and his BYU undergraduate student team are now working toward the development of drugs that specifically target NEK2. Their hope is to develop a compound that is minimally toxic to normal cells while having a high selectivity to cancer cells.

The Iowa-BYU research team is currently in the third year of a five-year National Institute of Health grant. The goal is to be ready to take newly formed compounds into human studies by the end of the grant period.

"This study shows convincingly that genomic changes over time are culprit in more aggressive cancer behavior,” said Dr. Rafael Fonseca, Chair of the Department of Medicine at Mayo Clinic in Arizona, who was not involved in the study. “It is likely that for cancers the major risk factors for poor prognosis are not the specific cancer genetic changes, but rather the ability of any given cancer to change, mutate and evolve."

A good portion of Professor Bearss’ contribution to this research study occurred while he was Co-Director of the Center for Investigational Therapeutics and an associate professor of oncology at the University of Utah’s Huntsman Cancer Institute. Collaborators Zhan and Tricot were also both formerly at the Huntsman Cancer Institute.

Dr. Tricot currently serves as the director of Holden Comprehensive Cancer Center’s Bone Marrow Transplant and Myeloma Program at University of Iowa Hospitals and Clinics.

Bearss joined BYU’s Department of Physiology and Developmental Biology in the fall of 2012, after three years as a professor at the Huntsman Cancer Institute.

Dr. Bearss also served on the faculty of the University of Arizona and has founded and led numerous pharmaceutical startup companies during his career.

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Professor David Bearss in his lab on the campus of BYU.

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Professor David Bearss in his lab on the campus of BYU.

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BYU researcher David Bearss is part of a team to pinpoint a gene that makes some cancers drug resistant.

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Professor David Bearss in his lab on the campus of BYU.

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Professor David Bearss and his students in his lab on the campus of BYU.
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