我们报告了一种以前未被认识的信号机制，它是用 BRAF 抑制剂治疗的 BRAF 突变黑色素瘤的药物耐受性的基础。其主要特征是由嘌呤能配体门控阳离子通道 P2X 受体启动的持续细胞内 Ca 2 信号传导。 Src 家族激酶充当细胞质 Ca 2 尖峰的介质，激活 ERK1/2，众所周知支持细胞存活和增殖。该网络的一个有趣特征是，细胞外 ATP 在生命系统中几乎无处不在，它是可以通过 P2X 通道启动 Ca 2 尖峰的配体。 ATP 在肿瘤微环境中含量丰富，并由垂死细胞释放，从而暗示药物敏感细胞的死亡是导致 ERK 重新激活和药物耐受的营养刺激来源。这种机制立即解释了 BRAF 突变黑色素瘤在接受 BRAFi 治疗后不可避免的复发。

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.