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Sci. Signal., 23 November 2010
Vol. 3, Issue 149, p. ra84
[DOI: 10.1126/scisignal.2001148]

RESEARCH ARTICLES

Editor's Summary

Making Resistance Futile
One of the lures of research into signal transduction is the possibility that it could lead to the development of highly targeted therapies that specifically interfere with pathways that are perturbed under pathological conditions. For instance, the discovery that mutations in BRAF are associated with various cancers led to the investigation of pharmacological inhibitors of BRAF—or the downstream kinase MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase)—as therapies for individuals with BRAF-mutant tumors. All too often, however, initial promising clinical responses to such targeted therapies are followed by relapse, as cancer cells develop resistance to a particular therapeutic agent. Corcoran et al. explored the mechanisms whereby BRAF-mutant colorectal cancer cells became resistant to a MEK inhibitor and discovered that resistance involved amplification of the mutant BRAF gene. Furthermore, they found that cancer cells resistant to inhibition of either MEK or BRAF alone remained sensitive to the combined inhibition of BRAF and MEK, undergoing apoptosis at low concentrations of the inhibitors. They thus propose that, in individuals with BRAF-mutant tumors, combined inhibition of MEK and BRAF could overcome resistance to targeted therapy—and perhaps prevent it from arising.

Citation: R. B. Corcoran, D. Dias-Santagata, K. Bergethon, A. J. Iafrate, J. Settleman, J. A. Engelman, BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation. Sci. Signal. 3, ra84 (2010).

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