BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner

Background: K-Ras mutation poses a particularly difficult problem for Cancer therapy. Activating mutations in K-Ras are common in cancers of the lung, pancreas, and colon and are associated with poor response to therapy. As such, targeted therapies that abrogate K-RAS-induced oncogenicity would be of tremendous value.

Methods: We searched for small molecule kinase inhibitors that preferentially affect the growth of colorectal Cancer cells expressing mutant K-Ras. The mechanism of action of one inhibitor was explored using chemical and genetic approaches.

Results: We identified BAY61-3606 as an inhibitor of proliferation in colorectal Cancer cells expressing mutant forms of K-Ras, but not in isogenic cells expressing wild-type K-Ras. In addition to its anti-proliferative effects in mutant cells, BAY61-3606 exhibited a distinct biological property in wild-type cells in that it conferred sensitivity to inhibition of Raf. In this context, BAY61-3606 acted by inhibiting MAP4K2 (GCK), which normally activates NFκβ signaling in wild-type cells in response to inhibition of Raf. As a result of MAP4K2 inhibition, wild-type cells became sensitive to AZ-628, a Raf Inhibitor, when also treated with BAY61-3606.

Conclusions: These studies indicate that BAY61-3606 exerts distinct biological activities in different genetic contexts.