BAY61-3606 Affects the Viability of Colon Cancer Cells in a Genotype-Directed Manner
Author(s)
Zhang, Tinghu; Kendall, Krystle R.; Gray, Nathanael S.; Haigis, Kevin M.; Lau, Ken S.; Lauffenburger, Douglas A; ... Show more Show less
DownloadLau-2012-BAY61-3606 Affects t.pdf (1.562Mb)
PUBLISHER_CC
Publisher with Creative Commons License
Creative Commons Attribution
Terms of use
Metadata
Show full item recordAbstract
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.
Date issued
2012-07Department
Massachusetts Institute of Technology. Department of Biological Engineering; Koch Institute for Integrative Cancer Research at MITJournal
PLoS ONE
Publisher
Public Library of Science
Citation
Lau, Ken S. et al. “BAY61-3606 Affects the Viability of Colon Cancer Cells in a Genotype-Directed Manner.” Ed. David J. Reiner. PLoS ONE 7.7 (2012): e41343.
Version: Final published version
ISSN
1932-6203