Researchers at the Moores Cancer Center at the University of California, San Diego (UCSD) believe they have found one reason that pancreatic cancer tumors are so difficult to treat with drugs. They found a molecular pathway mediated by a tyrosine kinase signaling protein, RON, which steps up pancreatic cancer cell survival and resistance to Eli Lilly’s Gemzar. The team also identified alternate routes cancer cells take to avoid the effects of the therapy.
The findings by a group led by Andrew M. Lowy, M.D., professor of surgery and chief of surgical oncology at the UCSD School of Medicine and the Moores UCSD Cancer Center, are reported online and will appear in the February 1 issue of Cancer Research. The paper is titled “Silencing of RON Receptor Signaling Promotes Apoptosis and Gemcitabine Sensitivity in Pancreatic Cancers.”
Previous work in Dr. Lowy's lab showed that RON is overexpressed in a majority of precancerous and pancreatic cancer cells. He also observed that RON could help cells resist dying. The researchers wanted to find out what role, if any, RON played in pancreatic cancer development and progression.
They were able to show that RON sends signals that regulate the activity of genes that help tumor cells survive, including Bcl-2 and the transcription factors signal transducer and activator of transcription 3 (STAT 3) and c-Jun. This implies that “RON is a potent survival signal for pancreatic cancer cells,” Dr. Lowy notes.
To see the effects of reducing or blocking RON activity, the team shut down RON expression in pancreatic cancer cells and then used those cells to establish tumors in mice. Those tumors were treated with Gemzar. Tumors in which RON was silenced were much more sensitive to the chemotherapy than the RON-expressing cancer cells, the scientists report.
Yet, the scientists found that the cancer cells and tumors were eventually able to bypass the silencing agent as well as the drug's effects and continued to grow. This was associated with re-expression of RON and/or expression of phosphorylated forms of the related c-Met or epidermal growth factor receptors. About 50% of the tumor cells re-expressed RON, according to the scientists.
“This is what most tumors do,” Dr. Lowy says, explaining that clinically, pancreatic cancer tumors often respond to therapy at first, only to begin growing again. “We know that diseases such as pancreatic cancer are too complex for one drug to be effective. If we can learn to predict the results of RON-directed therapy, maybe we can combine it with an EGFR-directed therapy, for example, to take away tumor escape routes.”
Dr. Lowy asserted the need to further study RON's part in pancreatic cancer development and progression. “We need to figure out which tumors are relying on RON. If we could develop biomarkers to identify which tumors are going to be susceptible to RON-targeted therapy, then we can begin to figure out what tumors do to escape such treatments.”