Purinergic Ca 2+ Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma.

Autor:	Stauffer, Philip E., Brinkley, Jordon, Jacobson, David A., Quaranta, Vito, Tyson, Darren R.
Předmět:	MELANOMA treatment PROTEIN kinase inhibitors RESEARCH funding CHEMICAL reagents CELLULAR signal transduction FLUORESCENT antibody technique DESCRIPTIVE statistics CELL culture CELL lines RNA GENE expression profiling DISEASE relapse GENETIC mutation DRUG tolerance SEQUENCE analysis
Zdroj:	Cancers; Jul2024, Vol. 16 Issue 13, p2426, 23p
Abstrakt:	Simple Summary: The treatment of BRAF-mutant melanoma with BRAF inhibitors is severely limited in clinical practice, in part due to the emergence of drug tolerance via non-genetic adaptation to therapies. Improving our understanding of the molecular mechanisms that underlie drug tolerance may lead to improved treatment strategies. Here, we describe a novel calcium-dependent signaling mechanism induced by BRAF inhibitor (BRAFi) treatment that provides compensatory mitogenic signaling to drug-tolerant persister cells in the form of MAPK reactivation. This calcium signaling mechanism has not previously been recognized in BRAFi-tolerant melanoma, may initiate a novel line of scientific inquiry, and presents a host of novel targets for therapeutic development in this field. 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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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