Stauffer Philip E, Brinkley Jordon, Jacobson David A, Quaranta Vito, Tyson Darren R
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Cancers (Basel). 2024 Jun 30;16(13):2426. doi: 10.3390/cancers16132426.
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 Ca signaling initiated by P2X7 receptors (purinergic ligand-gated cation channels) and an enhanced ability for these Ca signals to reactivate ERK1/2 in the drug-tolerant state. Extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca 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.
药物耐受性是癌症治疗后复发的主要原因。尽管进行了深入研究，但其分子基础仍知之甚少，这阻碍了可行的干预措施。我们报告了一种先前未被认识的信号传导机制，该机制支持用BRAF抑制剂治疗的BRAF突变型黑色素瘤中的药物耐受性，这可能与其他癌症普遍相关。其关键特征是由P2X7受体（嘌呤能配体门控阳离子通道）引发的细胞内源性细胞内钙信号传导，以及这些钙信号在药物耐受状态下重新激活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通道引发钙尖峰的配体。ATP在肿瘤微环境中含量丰富，由垂死细胞释放，具有讽刺意味的是，这意味着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源。这种机制立即解释了BRAF突变型黑色素瘤在BRAFi治疗后不可避免的复发，并指出了克服它的可行策略。
