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

Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) metho...

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Published in:British journal of cancer 2020-08, Vol.123 (4), p.556-567
Main Authors: Rausch, Magdalena, Weiss, Andrea, Achkhanian, Joanna, Rotari, Andrei, Nowak-Sliwinska, Patrycja
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis
Benzamides - pharmacology
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - genetics
Cell culture
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Drug dosages
Drug resistance
Drug Screening Assays, Antitumor
Enzyme inhibitors
Fibroblast growth factor receptors
Humans
Indazoles - pharmacology
Inhibitor drugs
Kidney cancer
Kidney Neoplasms - drug therapy
Kidney Neoplasms - genetics
Mathematical models
Metabolism
Models, Theoretical
Piperazines - pharmacology
Pyrazoles - pharmacology
Renal cell carcinoma
Signal transduction
Signal Transduction - drug effects
Small Molecule Libraries - pharmacology
Sulfonamides - pharmacology
Sunitinib - pharmacology
Targeted cancer therapy
Tumor cell lines
Tumors
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Summary:Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. 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). 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 co-culture models revealed significant inhibition of the spheroid growth (up to 95%). 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.
ISSN:0007-0920
1532-1827
DOI:10.1038/s41416-020-0890-y