Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma

Article Article scientifique Article Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma eng 2020 author Rausch Magdalena 897516 author Weiss Andrea author Achkhanian Joanna 856205 author Rotari Andrei 908897 author Nowak-Sliwinska Patrycja 848409 10.1038/s41416-020-0890-y 32439932 0007-0920 http://www.nature.com/articles/s41416-020-0890-y BACKGROUND: Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. METHODS: We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (−ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC). RESULTS: Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3- kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic coculture models revealed significant inhibition of the spheroid growth (up to 95%). CONCLUSION: We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development. Dewey 615 31 Section des sciences pharmaceutiques 17 false 1325 Pharmacologie moléculaire British Journal of Cancer 9cfddefa-6cc0-4b6b-87a4-d311014bca43 Article (Published version) Public Rauschetal2020BrJCancer.pdf 2189428 application/pdf CC BY openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma	British Journal of Cancer			2020	344	191

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Rotari, Andrei