title: Antitumour efficacy of the selumetinib and trametinib MEK inhibitors in a combined human airway-tumour-stroma lung cancer model.
abstract: With more than 1 million deaths worldwide every year, lung cancer remains an area of unmet need. Accessible human in vitro 3D tissue models are required to improve preclinical predictivity. OncoCilAir™ is a new in vitro model of Non Small Cell Lung Cancer which combines a reconstituted human airway epithelium, human lung fibroblasts and lung adenocarcinoma cell lines. Remarkably, we found that in this 3D microenvironment tumour cells expand by forming nodules, mimicking a human lung cancer feature. OncoCilAir™ mutated for KRAS and expressing the green fluorescent protein were used to test the antitumour potential of the investigational MEK inhibitors selumetinib and trametinib. As primary endpoint, changes in tumour size were assessed by fluorescence measurements. Tumours showed a reduced growth in response to the MEK inhibitors, but halting the selumetinib dosing resulted in tumour relapse. Importantly, toxicity study on the normal part of the cultures revealed that the airway epithelium integrity was also affected by anticancer drug treatments. These results highlight the possibility to assess simultaneously drug efficacy, drug side-effect and tumour recurrence within a single culture model. OncoCilAir™ heralds a new generation of integrated in vitro tumour models that should be valuable tools for drug development, while reducing animal testing.
authors.affiliation: OncoTheis Sàrl, 14 chemin des aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland. Electronic address: christophe.mas@oncotheis.com.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mas
authors.affiliation: OncoTheis Sàrl, 14 chemin des aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Bernadett
authors.initials: B
authors.lastname: Boda
authors.affiliation: Epithelix Sàrl, Plan-les-Ouates, Switzerland.
authors.forename: Mireille
authors.initials: M
authors.lastname: CaulFuty
authors.affiliation: Epithelix Sàrl, Plan-les-Ouates, Switzerland.
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.affiliation: Epithelix Sàrl, Plan-les-Ouates, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Wiszniewski
authors.affiliation: OncoTheis Sàrl, 14 chemin des aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland; Epithelix Sàrl, Plan-les-Ouates, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Constant
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008168:Lung / Q000166:cytology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib
keywords: 3D model; In vitro; Lung cancer; Preclinical; Tumour microenvironment