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Sci. Signal., 29 March 2011
Vol. 4, Issue 166, p. ra17
[DOI: 10.1126/scisignal.2001752]


Editor's Summary

Driving Resistance
The promise of using targeted small-molecule kinase inhibitors in treating cancer has been shadowed by the development of resistance to these drugs. Here, Little et al. used colorectal cancer cell lines with oncogenic mutations in either KRAS or BRAF—both of which lead to increased signaling through the ERK (extracellular signal–regulated kinase) signaling pathway—to investigate the mechanisms whereby cells developed resistance to AZD6244, a MEK1/2 (mitogen-activated or extracellular signal–regulated protein kinase kinases 1 and 2) inhibitor now in clinical trials. Rather than developing mutations in MEK1/2, cancer cells became resistant to MEK1/2 through amplification of the driving oncogene (oncogenic KRAS or BRAF) and a consequent increase in signaling through the ERK pathway. These observations have implications for the use of MEK1/2 inhibitors—and possibly other inhibitors that target downstream pathway components rather than the driving oncogene itself—in combination with other antineoplastic therapies.

Citation: A. S. Little, K. Balmanno, M. J. Sale, S. Newman, J. R. Dry, M. Hampson, P. A. W. Edwards, P. D. Smith, S. J. Cook, Amplification of the Driving Oncogene, KRAS or BRAF, Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal Cancer Cells. Sci. Signal. 4, ra17 (2011).

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