Purinergic Ca2+ Signaling as a Novel Mechanism of Drug Tolerance in BRAF-Mutant Melanoma.
Cancers (Basel)
; 16(13)2024 Jun 30.
Article
in En
| MEDLINE
| ID: mdl-39001489
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Cancers (Basel)
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos