MEK1F53L mutation drives clinical acquired resistance to combined RAF/MEK inhibition. MEK1F53L mutation drives clinical acquired resistance to combined.

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Presentation transcript:

MEK1F53L mutation drives clinical acquired resistance to combined RAF/MEK inhibition. MEK1F53L mutation drives clinical acquired resistance to combined RAF/MEK inhibition. A, clinical time course of therapy for patient #3 with BRAF-mutant colorectal cancer showing dates of therapy and timing of postprogression biopsy. Cumulative tumor diameter as measured by RECIST is shown throughout the treatment course. B, list of key mutations identified in the postprogression biopsy with associated allele frequencies. C, Sanger sequencing of a patient-derived cell line generated from the postprogression biopsy for BRAFV600E, ARAFQ489L, and MEK1F53L. All mutations were found to be present in 30 of 30 single-cell clones. D, cells expressing the indicated constructs were treated with dabrafenib (DAB) plus trametinib (TRA) or VX-11e (VX) as shown for 72 hours, and relative cell titer was determined. E, cells expressing wild-type MEK1 (MEK1WT), MEK1F53L, or empty vector control were treated with the indicated concentrations of drugs for 24 hours, and Western blotting was performed with the indicated antibodies. Leanne G. Ahronian et al. Cancer Discovery 2015;5:358-367 ©2015 by American Association for Cancer Research