Cancer cells reactivate this pathway in response to drug treatment in two distinct ways, as revealed by mechanistic studies: (1) increasing the amount of active Ras in the cell, which results in paradoxical activation of ERK signaling, and (2) alternatively splicing BRAF (V600E) to produce variants with a truncated N-terminus, which enhances BRAF (V600E) homodimerization and reduces drug affinity. Here, BRAF is linked to cancer.