耐药性是癌症治疗后复发的主要原因。尽管付出了巨大的努力，但其分子基础仍然知之甚少，阻碍了可采取行动的干预措施。我们报告了一种以前未被认识的信号机制，支持用 BRAF 抑制剂治疗的 BRAF 突变黑色素瘤的药物耐受性，该机制可能与其他癌症普遍相关。其主要特征是由 P2X7 受体（嘌呤能配体门控阳离子通道）启动的细胞固有的细胞内 Ca2 信号传导，以及这些 Ca2 信号在耐药状态下重新激活 ERK1/2 的能力增强。细胞外 ATP 在生命系统中几乎无处不在，是可以通过 P2X7 通道启动 Ca2 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，讽刺的是，治疗引发的癌细胞死亡是导致 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，并指出了克服它的可行策略。

Drug tolerance is a major cause of relapse after cancer treatment. Despite intensive efforts, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors that could be of general relevance to other cancers. Its key features are cell-intrinsic intracellular Ca2+ signaling initiated by P2X7 receptors (purinergic ligand-gated cation channels) and an enhanced ability for these Ca2+ signals to reactivate ERK1/2 in the drug-tolerant state. Extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca2+ spikes via P2X7 channels. ATP is abundant in the tumor microenvironment and is released by dying cells, ironically implicating treatment-initiated cancer cell death 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 and points to actionable strategies to overcome it.