文章：

嘌呤能Ca2+信号传导作为BRAF突变黑色素瘤药物耐受的新机制

Purinergic Ca2+Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma

原文发布日期：30 June 2024

DOI: 10.3390/cancers16132426

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

药物耐受是癌症治疗后复发的主要原因。尽管已付出巨大努力，但其分子机制仍不甚明确，阻碍了有效干预措施的开发。本研究揭示了一种先前未被识别的信号传导机制，该机制支持BRAF突变型黑色素瘤在接受BRAF抑制剂治疗时产生药物耐受性，且可能对其他癌症具有普遍意义。该机制的核心特征包括：由P2X7受体（嘌呤能配体门控阳离子通道）启动的细胞固有性细胞内钙离子信号传导，以及这些钙信号在药物耐受状态下重新激活ERK1/2的增强能力。作为生命系统中几乎无处不在的配体，细胞外ATP可通过P2X7通道引发钙离子峰。肿瘤微环境中富含ATP，且ATP可由死亡细胞释放——具有讽刺意味的是，治疗引发的癌细胞死亡反而成为营养刺激的来源，导致ERK重新激活和药物耐受。这一机制直接解释了BRAF突变型黑色素瘤经BRAF抑制剂治疗后不可避免的复发问题，并为克服该问题指明了可操作的干预策略。

原文链接：

Purinergic Ca2+Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma