title: Differential effects of MAPK pathway inhibitors on migration and invasiveness of BRAF(V600E) mutant thyroid cancer cells in 2D and 3D culture.
abstract: Tumor microenvironment influences targeted drug therapy. In this study we compared drug responses to RAF and MEK inhibitors on tumor cell migration in 2D and 3D culture of BRAF(V600E) mutant cell lines derived from human papillary (BCPAP) and anaplastic (SW1736) thyroid carcinomas. Scratch wounding was compared to a double-layered collagen gel model developed for analysis of directed tumor cell invasion during prolonged culture. In BCPAP both PLX4720 and U0126 inhibited growth and migration in 2D and decreased tumor cell survival in 3D. In SW1736 drugs had no effect on migration in 2D but decreased invasion in 3D, however this related to reduced growth. Dual inhibition of BRAF(V600E) and MEK reduced but did not prevent SW1736 invasion although rebound phosphorylation of ERK in response to PLX4720 was blocked by U0126. These findings indicate that anti-tumor drug effects in vitro differ depending on culture conditions (2D vs. 3D) and that the invasive features of anaplastic thyroid cancer depend on non-MEK mechanism(s).
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. Electronic address: camilla.ingeson@gu.se.
authors.forename: Camilla
authors.initials: C
authors.lastname: Ingeson-Carlsson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. Electronic address: angela.martinez-monleon@gu.se.
authors.forename: Angela
authors.initials: A
authors.lastname: Martinez-Monleon
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. Electronic address: mikael.nilsson@gu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Nilsson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D007211:Indoles; D009570:Nitriles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C113580:U 0126; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: 3D; BRAF; Cancer; MEK; Migration; PLX4720; Thyroid; U0126