BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy |
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| Authors: | Douglas B Johnson Merrida A Childress Zachary R Chalmers Garrett M Frampton Siraj M Ali Samuel M Rubinstein David Fabrizio Jeffrey S Ross Sohail Balasubramanian Vincent A Miller Philip J Stephens Christine M Lovly |
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| Institution: | 1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;2. Department of Medicine, Nashville, TN, USA;3. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA;4. Department of Cancer Biology, Nashville, TN, USA;5. Foundation Medicine Inc., Cambridge, MA, USA |
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| Abstract: | BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV600‐mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2–8, which includes the Ras‐binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS‐RAF‐MEK‐ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition. |
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| Keywords: | BRAF dabrafenib internal deletion rearrangement resistance trametinib vemurafenib |
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