Organotypic three-dimensional cancer cell cultures mirror drug responses in vivo: lessons learned from the inhibition of EGFR signaling
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Nico Jacobi1, Rita Seeboeck2, Elisabeth Hofmann2, Helmut Schweiger1, Veronika Smolinska1, Thomas Mohr3, Alexandra Boyer1, Wolfgang Sommergruber4, Peter Lechner5, Corina Pichler-Huebschmann5, Kamil Önder6,7, Harald Hundsberger2, Christoph Wiesner2 and Andreas Eger1,2
1IMC University of Applied Sciences Krems, Department Life Sciences, Research Institute for Applied Bioanalytics and Drug Development, A-3500 Krems, Austria
2IMC University of Applied Sciences Krems, Department Life Sciences, Institute of Medical and Pharmaceutical Biotechnology, A-3500 Krems, Austria
3Medical University of Vienna, Institute for Cancer Research, A-1090 Vienna, Austria
4Boehringer Ingelheim, RCV GmbH and Co KG, A-1121 Vienna, Austria
5University Clinic Tulln, Department Surgery, A-3430 Tulln, Austria
6Research Program for Rational Drug Design in Dermatology and Rheumatology, Department of Dermatology, Paracelsus Medical University of Salzburg, A-5020 Salzburg, Austria
7ProComCure Biotech, A-5081 Anif, Austria
Andreas Eger, email: firstname.lastname@example.org
Keywords: drug discovery; 3D models; ERBB signaling; targeted drugs; oncogene addiction
Received: August 25, 2017 Accepted: October 27, 2017 Published: November 17, 2017
Complex three-dimensional (3D) in vitro models that recapitulate human tumor biology are essential to understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellular communication, nutrient and oxygen gradients, and cell polarity that is lacking in two-dimensional (2D) monolayer cultures. In the present study, we demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of ErbB family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments.
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