A new tumor-promoting pathway

The ERK pathway plays a critical role in embryonic development and tissue repair because it instructs cells to multiply and start dividing, but when over activated cancer growth occurs.

While investigating a potential therapeutic target for the ERK1 and 2 pathway, a widely expressed signaling molecule known to drive cancer growth in one third of patients with colorectal cancer, University of California San Diego School of Medicine researchers found that an alternative pathway immediately emerges when ERK1/2 is halted, thus allowing tumor cell proliferation to continue.

In a paper published in the journal Nature Communications, researchers report that treating both ERK1/2 and the compensatory pathway, ERK5, concurrently with a combination of drug inhibitors halted colorectal cancer growth more effectively in both mouse models and human colorectal cancer cell lines.

Researchers show that loss of Erk1/2in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms.

Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. 

"Therapies aimed at targeting ERK1/2 likely fail because this mechanism is allowing proliferation through a different pathway," said senior author. "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."

http://www.eurekalert.org/pub_releases/2016-05/uoc--bkc051716.php