| Autor: |
Berndsen RH; Molecular Pharmacology Group, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Rue Michel-Servet 1, 1211 Geneva, Switzerland.; Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC-Location VUmc, VU University Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands., Swier N; Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC-Location VUmc, VU University Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands., van Beijnum JR; Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC-Location VUmc, VU University Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands., Nowak-Sliwinska P; Molecular Pharmacology Group, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Rue Michel-Servet 1, 1211 Geneva, Switzerland.; Translational Research Center in Oncohaematology, Rue Michel-Servet 1, 1211 Geneva, Switzerland. |
| Abstrakt: |
Patients with advanced colorectal cancer (CRC) still depend on chemotherapy regimens that are associated with significant limitations, including resistance and toxicity. The contribution of tyrosine kinase inhibitors (TKIs) to the prolongation of survival in these patients is limited, hampering clinical implementation. It is suggested that an optimal combination of appropriate TKIs can outperform treatment strategies that contain chemotherapy. We have previously identified a strongly synergistic drug combination (SDC), consisting of axitinib, erlotinib, and dasatinib that is active in renal cell carcinoma cells. In this study, we investigated the activity of this SDC in different CRC cell lines (SW620, HT29, and DLD-1) in more detail. SDC treatment significantly and synergistically decreased cell metabolic activity and induced apoptosis. The translation of the in-vitro-based results to in vivo conditions revealed significant CRC tumor growth inhibition, as evaluated in the chicken chorioallantoic membrane (CAM) model. Phosphoproteomics analysis of the tested cell lines revealed expression profiles that explained the observed activity. In conclusion, we demonstrate promising activity of an optimized mixture of axitinib, erlotinib, and dasatinib in CRC cells, and suggest further translational development of this drug mixture. |
