BAY61-3606 Affects the Viability of Colon Cancer Cells in a Genotype-Directed MannerReportar como inadecuado




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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.



Autor: Ken S. Lau, Tinghu Zhang, Krystle R. Kendall, Douglas Lauffenburger, Nathanael S. Gray, Kevin M. Haigis

Fuente: http://plos.srce.hr/



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