Purinergic calcium signaling drives drug tolerance through ERK reactivation in BRAF-mutant melanoma.

We report a previously unrecognized signaling mechanism underlying drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors. Its key feature is sustained intracellular Ca 2+ signaling initiated by purinergic ligand-gated cation channels, P2X receptors. Src family kinases act as mediators for cytoplasmic Ca 2+ spikes to activate ERK1/2, well-known to support cell survival and proliferation. An intriguing feature of this network is that extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca 2+ spikes via P2X channels. ATP is abundant in the tumor microenvironment and is released by dying cells, thereby implicating the death of drug-sensitive cells as a source of trophic stimuli that leads to ERK reactivation and drug tolerance. Such a mechanism immediately offers an explanation of the inevitable relapse after BRAFi treatment in BRAF-mutant melanoma.