In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells.
Oncol Rep
; 37(3): 1367-1378, 2017 Mar.
Article
in En
| MEDLINE
| ID: mdl-28098866
ABSTRACT
The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. In the present study we describe a different resistance mechanism. After several weeks of longterm in vitro treatment of two different V600E BRAFmutated melanoma cell lines with MARK inhibitors, PLX4032 and/or GDC-0973, the majority of the cells died whereas some remained viable and quiescent (SUR). Markedly, discontinuing treatment of SUR cells with MAPK inhibitors allowed the population to regrow and these cells retained drug sensitivity equal to that of the parental cells. SUR cells had increased expression levels of CD271 and ABCB5 and presented senescence-associated characteristics. Notably, SUR cells were efficiently lysed by cytotoxic T lymphocytes recognizing MART-1 and gp100 melanoma differentiation antigens. We propose quiescent plasticity as a mechanism of resistance to BRAF and MEK inhibitors while retaining sensitivity to immune effectors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperidines
/
Sulfonamides
/
Azetidines
/
CD8-Positive T-Lymphocytes
/
Drug Resistance, Neoplasm
/
MAP Kinase Signaling System
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Indoles
/
Melanoma
Type of study:
Diagnostic_studies
/
Prognostic_studies
Language:
En
Journal:
Oncol Rep
Journal subject:
NEOPLASIAS
Year:
2017
Document type:
Article
Affiliation country: