Wayne State University

WSU/KCI researchers identify novel pathway in lung cancer to make chemotherapy more effective

ORLANDO, Fla. – Scientists from Wayne State University and the Barbara Ann Karmanos Cancer Institute in Detroit presented a study at the American Association for Cancer Research’s 102nd Annual Meeting 2011 that identifies a key enzyme in non-small cell lung cancers that could potentially make standard chemotherapy more effective against this highly deadly disease.

The presentation, “Ubiquitination of RRM1 by Ring1B (RNF2) promotes its degradation and nuclear export,” was presented by Yingtao Zhang, M.D., Ph.D., research scientist with Karmanos and Wayne State University's School of Medicine (WSU SOM).

Her fellow co-authors are Xin Li, M.D., research associate in the Department of Oncology at Karmanos and WSU SOM; Zhengming Chen, Ph.D., assistant professor in the Department of Oncology at Karmanos and WSU SOM; Scott N. Freeman, Ph.D., a former post-doctoral fellow at H. Lee Moffitt Cancer Center now with the Federal Drug Administration; Jun Zhou, M.D., a research scientist formerly with Moffitt Cancer Center; and Gerold Bepler, M.D., Ph.D., Karmanos president and CEO and interim chair of the Department of Oncology at WSU SOM. The research also will be published in the 2011 Proceedings of the American Association for Cancer Research.

The study explored the role of RRM1 (ribonucleotide reductase M1), a key enzyme involved in tumor suppression and one that plays an essential role in the development of lung cancer. It has a dual nature in that while it suppresses tumors, overexpression of RRMI is strongly associated with gemcitabine resistance in various cancers, making chemotherapy less effective.

“The purpose of our research is to investigate the mechanisms that control RRM1 expression and subcellular localization, which are extremely important to understanding RRM1 functions and potentially therapeutic applications,” said Dr. Zhang. “RRM1 is crucial for DNA damage repair and effectiveness of the chemotherapy agent gemcitabine. Examining the ubiquitination pathway – a pathway through which cellular proteins (i.e. RRM1) are degraded – may therefore have therapeutic value.

“This is a totally new research study that hasn’t been done anywhere else.”

Gemcitabine, described by researchers as a “blockbuster” drug, is used in the treatment of non-small cell lung cancer, along with various other carcinomas including pancreatic, bladder and breast cancer. It is also being investigated for use in esophageal cancer and is used experimentally in lymphomas and various other tumor types.

Researchers have identified a ubiquitin E3 ligase, Ring1B, a protein associated with RRM1. It is one of the most important E3 ligases in the ubiquitination pathway, which plays an essential role in directing the fate and function of many cellular proteins, such as histone H2A, a protein associated with DNA. They also found the protein level of RRM1 is regulated by a proteasome-mediated degradation pathway (i.e. ubiquitination pathway). They discovered that Ring1B is involved in the ubiquitination of RRM1 which leads to RRM1 degradation and translocation from a cell’s nucleus to cytoplasm, located outside the nucleus.

The team is continuing its work in understanding whether Ring1B breaks down RRM1 completely so that cancer cells can be destroyed by gemcitabine. Dr. Zhang, however, noted that the complete inhibition of RRM1 and its expression induces cancer cell death.

“It is demonstrated that reduction of RRM1 level can reverse resistance and sensitizes tumor cells to gemcitabine, implicating that targeting the ubiquitination pathway may potentially be effective in treatment of gemcitabine-resistant lung cancer.” she said.

Researchers have been studying the ubiquitination of RRM1 for more than two years, headed by Dr. Bepler, who joined the Karmanos Cancer Institute as president and CEO in February 2010. Dr. Bepler said that better therapies must be developed so that non-small cell lung cancer patients derive better outcomes.

“Non-Small Cell Lung Cancer is very difficult to treat,” he said. “The usual response rates for patients are about 25 percent, so approximately three-quarters of those patients have very little if any benefit from certain treatments. Knowing up-front which treatment will and will not work allows us to use a targeted therapy that provides the most benefit to the patient for their specific cancer.”