1. BRAF amplification causes clinical acquired resistance to combined RAF/EGFR inhibition.
BRAF amplification causes clinical acquired resistance to combined RAF/EGFR inhibition. A, clinical time course of therapy for patient #2 with BRAF-mutant colorectal cancer showing dates of therapy and timing of postprogression biopsy. CEA tumor marker levels and cumulative tumor diameter as measured by RECIST are shown throughout the treatment course. B, DNA copy-number traces are shown for the postprogression biopsy compared with a pretreatment biopsy taken from the same lesion immediately before the start of panitumumab + dabrafenib therapy. Focal amplification of BRAF on chromosome 7 is shown in the postprogression biopsy. BRAFV600E mutant allele frequencies are shown for each sample. CR, copy ratio. C, FISH was performed on the pretreatment and postprogression biopsies using probes for BRAF (red) and chromosome 7 (Chr7; green). D, VACO432 cells overexpressing BRAFV600E compared with empty vector were lysed, and Western blotting was performed with the indicated antibodies. E, cells from D were treated for 72 hours with the indicated concentrations of dabrafenib (DAB), panitumumab (PAN), trametinib (TRA), or VX-11e (VX) for 72 hours, and relative cell titer was determined. F, cells from D were treated for 24 hours with the indicated concentrations of drugs, and Western blotting was performed with the indicated antibodies.
Leanne G. Ahronian et al. Cancer Discovery 2015;5:
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