In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells.

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 long‑term in vitro treatment of two different V600E BRAF‑mutated 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.
Authors	Florencia Paula Madorsky Rowdo, Antonela Barón, Erika María von Euw, José Mordoh
Journal	Oncology reports (Oncol Rep) Vol. 37 Issue 3 Pg. 1367-1378 (Mar 2017) ISSN: 1791-2431 [Electronic] Greece
PMID	28098866 (Publication Type: Journal Article)
Chemical References	Azetidines Enzyme Inhibitors Indoles MART-1 Antigen Piperidines RNA, Messenger Sulfonamides gp100 Melanoma Antigen Vemurafenib Mitogen-Activated Protein Kinases cobimetinib
Topics	Animals Apoptosis (drug effects) Azetidines (pharmacology) Blotting, Western CD8-Positive T-Lymphocytes (drug effects, immunology, pathology) Cell Cycle (drug effects) Cell Proliferation (drug effects) Drug Resistance, Neoplasm (drug effects) Enzyme Inhibitors (pharmacology) Flow Cytometry Humans Immunoenzyme Techniques In Vitro Techniques Indoles (pharmacology) MAP Kinase Signaling System (drug effects) MART-1 Antigen (genetics, metabolism) Melanoma (drug therapy, immunology, metabolism, pathology) Mice Mice, Inbred NOD Mice, SCID Mitogen-Activated Protein Kinases (antagonists & inhibitors) Piperidines (pharmacology) RNA, Messenger (genetics) Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Sulfonamides (pharmacology) T-Lymphocytes, Cytotoxic (drug effects, immunology, pathology) Tumor Cells, Cultured Vemurafenib Xenograft Model Antitumor Assays gp100 Melanoma Antigen (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!