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A curious biochemical consequence of BRAF inhibition (BRAFi) in BRAF-normal cells is paradoxical ERK pathway activation. This is a major mechanism by which RAS-mutant tumors are accelerated, as seen in BRAFi-driven cutaneous squamous cell carcinoma (SCC) and in the acceleration of mutant RAS-driven leukemia. This effect appears to be universal with the first-generation RAF inhibitors vemurafenib and dabrafenib, which facilitate RAF dimerization and thus signal activation, particularly in RAS-activated cells.
These authors report the development of a second generation of BRAF inhibitors, so-called paradox breakers that do not exhibit paradoxical ERK activation. PLX7904 and PLX8394 resemble vemurafenib structurally and show similar potency aga…