UC San Diego

Although the ERK1/2 MAPK signaling axis has been extensively studied, the mechanisms underlying acquired resistance to inhibitors targeting this pathway in colorectal cancer (CRC) remain poorly understood. Here, we describe not only a previously undefined homeostatic role for ERK1/2 in the maintenance of the intestinal epithelium, but also a novel compensatory role for ERK5/BMK1 in sustaining cellular proliferation of intestinal epithelial cells (IEC) in the absence of ERK1/2 signaling. First, we employed compound genetically engineered mice with a Vil- CreERT2;Erk1-/-;Erk2fl/fl genotype ("[delta] IEC mice"), thereby generating a conditional and inducible deletion of Erk2 only in IEC. [Delta]IEC mice showed severe enterocyte dysfunction, defective maturation and migration of secretory cell types, and hyper-proliferation of the epithelium, all culminating in dramatic disruption of crypt-villus architecture and intestinal function; these mice were moribund by a mere 10-12 days after knockout induction from malabsorption. We found the nature of this hyper-proliferation to be the compensatory activation of an alternative MAPK pathway, ERK5, thereby sustaining proliferation upon the loss of ERK1/2. These findings were replicated in human cancer cell lines by inhibitor treatment with MEK1/2 inhibitor, PD0325901, and in mouse primary small intestinal organoids isolated from [delta]IEC mice. We lastly found that ERK5 is a requirement for cell proliferation using ERK5 inhibitor, XMD8-92, in human cancer cell lines and intestinal organoids, observing total loss of proliferation and regression of mature organoids to a spheroid morphology. Together, these findings implicate targeting of ERK5 could work synergistically with inhibition of the MEK1/2-ERK1/2 axis to suppress proliferation of tumors in CRC