Making ERK work as a therapeutic target for colorectal cancer
Colorectal cancer is the third most common cancer in the US, affecting 1.2 million people. Despite extensive research, the five-year survival rate remains below 15%, underscoring the need for new treatments.
One-third of colorectal cancers are driven by over-activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which regulates proliferation, metabolism, and cell movement. However, drugs targeting the ERK1/2 pathway are not widely used to treat colorectal cancer because they don’t appreciably slow cancer growth. New research co-led by Petrus de Jong, M.D., Ph.D., postdoctoral associate at SBP, points to a possible reason for this lack of effect, as well as a solution.
“We genetically deleted the ERK1/2 pathway in the lining of the mouse intestine, and we expected to see less cell proliferation,” said de Jong, a co-first author on the paper. “Instead, the opposite occurred. There was more cell growth and the cells were less organized.” de Jong works in the laboratory of Garth Powis, D.Phil., professor and director of SBP’s NCI-Designated Cancer Center, who also contributed to the investigation.
The new study, published in Nature Communications, shows that the increased cell growth caused by disabling ERK1/2 results from increased activity of a related kinase, ERK5. The team went on to show that inhibiting both pathways suppresses proliferation of human colorectal cancer cell lines and slows growth of tumor-like structures in vitro.
“Therapies aimed at targeting ERK1/2 likely fail because ERK5 compensates,” said Eyal Raz, M.D., senior author and professor at the UC San Diego School of Medicine. “Previously, ERK5 didn’t seem important in colorectal cancer. This is an underappreciated escape pathway for tumor cells. Hence, the combination of ERK1/2 and ERK5 inhibitors may lead to more effective treatments for colorectal cancer patients.”
“If you block one pathway, cancer cells usually mutate and find another pathway that ultimately allows for a recurrence of cancer growth,” said Koji Taniguchi, M.D., Ph.D., assistant project scientist at UC San Diego and the other co-first author. “Usually, mutations occur over weeks or months. But other times, as in this case, the tumor does not need to develop mutations to find an escape route from targeted therapy. When you find the compensatory pathway and block both, there is no more escape.”
The scientists suggested that other inhibitors of the ERK1/2 pathway should be tested with ERK5 inhibitors in both human colorectal cancer cells and mouse models to identify the most effective combination that could advance to clinical trials.
This post is a modified version of the press release from UC San Diego. Photo from Ed Uthman via Flickr.
The paper is available online here.