Organs-on-a-chip or microphysiological systems (MPS) are increasingly contributing to the preclinical characterization of mode of action and adverse events of drug candidates. The recent advent of robust human multi-organ-chip systems enables the establishment of co-cultures of human drug target tissues with healthy organ equivalents prone to off-target effects of the respective drug. The prediction of side effects, such as those occurring in the skin during cancer therapies with antibodies against the epithelial growth factor receptor (EGFR), is currently not possible in conventional in vitro systems and limited in existing animal models due to phylogenetic differences between species.

Here we present a chip-based 5-day co-culture of human lung tumour spheroids (mucoepidermoid carcinoma H292) and human skin equivalents. We investigated the impact of repeated cetuximab exposure, an antibody against the EGF receptor to the co-culture and compared it with the effects on individual tissue cultures. Cetuximab showed an increased pro-apoptotic related gene expression in the tumor microtissues, and, simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated. Additionally, we compared the tumor-target related antibody effects with response data for afatinib - a small molecule EGFR inhibitor. Cetuximab showed an increased pro-apoptotic related gene expression in the tumor microtissues, and, simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated.

The described MPS has the potential to provide a single platform for in vitro evaluation of the therapeutic window of drug candidates.

Citation Format: Juliane Huebner, Marian Raschke, Katharina Schimek, Isabel Ruetschle, Sarah Graessle, Susanne Schnurre, Roland Lauster, Ilka Maschmeyer, Thomas Steger-Hartmann, Uwe Marx. Evaluation of EGFR induced on-target and target-mediated adverse effects in a 3D human lung tumour/skin microphysiological co-culture system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-027.