Blocking the ERK1/2 pathway and the compensatory ERK5 pathway stopped the growth of colorectal tumors.
In a recent study, researchers discovered that blocking the ERK1/2 pathway causes another pathway to emerge immediately, allowing colorectal tumors to continue growing.
The ERK1/2 pathway is a widely expressed signaling molecule that drives cancer growth in approximately one-third of patients with colorectal cancer, according to the study published in Nature communications.
"Since we were genetically deleting the ERK1/2 pathway, we expected to see less cell proliferation," said study co-first author of Petrus R. de Jong, MD, PhD. "Instead, the opposite occurred. There was more cell growth and loss of organization within the cells."
Researchers found that inhibiting both the ERK1/2 pathway ERK5 secondary pathway stopped colorectal cancer growth in mouse models, as well as in human colorectal cancer lines. The ERK pathway instructs cells to multiply and divide, so it is important for embryonic development and tissue repair, but over-activation causes cancer growth.
"Therapies aimed at targeting ERK1/2 likely fail because this mechanism is allowing proliferation through a different pathway," said study senior author Eyal Raz, MD. "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."
Prior to any patient trials, the researchers said they need to test other classes of inhibitors with ERK5 inhibitors in preclinical mouse models.
"If you block one pathway, cancer cells usually mutate and find another pathway that ultimately allows for a recurrence of cancer growth," concluded co-first author Koji Taniguchi, MD, PhD. "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."