{Reference Type}: Journal Article
{Title}: Purinergic Ca2+ Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma.
{Author}: Stauffer PE;Brinkley J;Jacobson DA;Quaranta V;Tyson DR;
{Journal}: Cancers (Basel)
{Volume}: 16
{Issue}: 13
{Year}: 2024 Jun 30
{Factor}: 6.575
{DOI}: 10.3390/cancers16132426
{Abstract}: 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.