BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy

Abstract

BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAF^V600- mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pre-treatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAF^V600E 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; 9 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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