title: 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.affiliation: Leloir Institute, IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Florencia Paula
authors.initials: FP
authors.lastname: Madorsky Rowdo
authors.affiliation: Leloir Institute, IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: Antonela
authors.initials: A
authors.lastname: Barón
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
authors.forename: Erika María
authors.initials: EM
authors.lastname: von Euw
authors.affiliation: Leloir Institute, IIBBA-CONICET, Buenos Aires, Argentina.
authors.forename: José
authors.initials: J
authors.lastname: Mordoh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines / Q000494:pharmacology*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D058965:MART-1 Antigen / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000378:metabolism
chemical_list: D001384:Azetidines; D004791:Enzyme Inhibitors; D007211:Indoles; D058965:MART-1 Antigen; D010880:Piperidines; D012333:RNA, Messenger; D013449:Sulfonamides; D058951:gp100 Melanoma Antigen; D000077484:Vemurafenib; D020928:Mitogen-Activated Protein Kinases; C574276:cobimetinib