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Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment

SIMPLE SUMMARY: Renal cell carcinoma (RCC) cancer is among the ten most common malignancies, and frequently presents as metastatic disease (mRCC). For these patients, systemic treatment is in order, but mRCC is often highly heterogeneous, and resistant to conventional therapies, or acquires resistan...

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Autores principales: van Beijnum, Judy R., Weiss, Andrea, Berndsen, Robert H., Wong, Tse J., Reckman, Louise C., Piersma, Sander R., Zoetemelk, Marloes, de Haas, Richard, Dormond, Olivier, Bex, Axel, Henneman, Alexander A., Jimenez, Connie R., Griffioen, Arjan W., Nowak-Sliwinska, Patrycja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564658/
https://www.ncbi.nlm.nih.gov/pubmed/32967224
http://dx.doi.org/10.3390/cancers12092697
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author van Beijnum, Judy R.
Weiss, Andrea
Berndsen, Robert H.
Wong, Tse J.
Reckman, Louise C.
Piersma, Sander R.
Zoetemelk, Marloes
de Haas, Richard
Dormond, Olivier
Bex, Axel
Henneman, Alexander A.
Jimenez, Connie R.
Griffioen, Arjan W.
Nowak-Sliwinska, Patrycja
author_facet van Beijnum, Judy R.
Weiss, Andrea
Berndsen, Robert H.
Wong, Tse J.
Reckman, Louise C.
Piersma, Sander R.
Zoetemelk, Marloes
de Haas, Richard
Dormond, Olivier
Bex, Axel
Henneman, Alexander A.
Jimenez, Connie R.
Griffioen, Arjan W.
Nowak-Sliwinska, Patrycja
author_sort van Beijnum, Judy R.
collection PubMed
description SIMPLE SUMMARY: Renal cell carcinoma (RCC) cancer is among the ten most common malignancies, and frequently presents as metastatic disease (mRCC). For these patients, systemic treatment is in order, but mRCC is often highly heterogeneous, and resistant to conventional therapies, or acquires resistance over time. Application of a combination of targeted therapeutic agents can tackle these problems, however, experimental optimization is not feasible given the enormous number of possible drug- and dose-combinations. We used a phenotypic approach, the streamlined-feedback system control (s-FSC) technique, which does not use a priori information on the mechanism of action of drugs. Using a number of searches, this method selects for optimized drug combinations (ODC) given at low doses (ED(5-25)), that can act synergistically. This way, we selected effective ODC for different RCC cell lines. Analysis of kinase activity was performed to provide mechanistic insight into the ODC action, and to further improve the found drug combinations. ABSTRACT: Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps. Phosphoproteomics analysis coupled to kinase activity analysis using the novel INKA (integrative inferred kinase activity) pipeline was performed to evaluate ODC mechanisms in a panel of renal cell carcinoma (RCC) cell lines. We identified different ODC with up to 95% effectivity for each RCC cell line, with low doses (ED(5–25)) of individual drugs. Global phosphoproteomics analysis demonstrated inhibition of relevant kinases, and targeting remaining active kinases with additional compounds improved efficacy. In addition, we identified a common RCC ODC, based on kinase activity data, to be effective in all RCC cell lines under study. Combining s-FSC with a phosphoproteomic profiling approach provides valuable insight in targetable kinase activity and allows for the identification of superior drug combinations for the treatment of RCC.
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spelling pubmed-75646582020-10-29 Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment van Beijnum, Judy R. Weiss, Andrea Berndsen, Robert H. Wong, Tse J. Reckman, Louise C. Piersma, Sander R. Zoetemelk, Marloes de Haas, Richard Dormond, Olivier Bex, Axel Henneman, Alexander A. Jimenez, Connie R. Griffioen, Arjan W. Nowak-Sliwinska, Patrycja Cancers (Basel) Article SIMPLE SUMMARY: Renal cell carcinoma (RCC) cancer is among the ten most common malignancies, and frequently presents as metastatic disease (mRCC). For these patients, systemic treatment is in order, but mRCC is often highly heterogeneous, and resistant to conventional therapies, or acquires resistance over time. Application of a combination of targeted therapeutic agents can tackle these problems, however, experimental optimization is not feasible given the enormous number of possible drug- and dose-combinations. We used a phenotypic approach, the streamlined-feedback system control (s-FSC) technique, which does not use a priori information on the mechanism of action of drugs. Using a number of searches, this method selects for optimized drug combinations (ODC) given at low doses (ED(5-25)), that can act synergistically. This way, we selected effective ODC for different RCC cell lines. Analysis of kinase activity was performed to provide mechanistic insight into the ODC action, and to further improve the found drug combinations. ABSTRACT: Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps. Phosphoproteomics analysis coupled to kinase activity analysis using the novel INKA (integrative inferred kinase activity) pipeline was performed to evaluate ODC mechanisms in a panel of renal cell carcinoma (RCC) cell lines. We identified different ODC with up to 95% effectivity for each RCC cell line, with low doses (ED(5–25)) of individual drugs. Global phosphoproteomics analysis demonstrated inhibition of relevant kinases, and targeting remaining active kinases with additional compounds improved efficacy. In addition, we identified a common RCC ODC, based on kinase activity data, to be effective in all RCC cell lines under study. Combining s-FSC with a phosphoproteomic profiling approach provides valuable insight in targetable kinase activity and allows for the identification of superior drug combinations for the treatment of RCC. MDPI 2020-09-21 /pmc/articles/PMC7564658/ /pubmed/32967224 http://dx.doi.org/10.3390/cancers12092697 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
van Beijnum, Judy R.
Weiss, Andrea
Berndsen, Robert H.
Wong, Tse J.
Reckman, Louise C.
Piersma, Sander R.
Zoetemelk, Marloes
de Haas, Richard
Dormond, Olivier
Bex, Axel
Henneman, Alexander A.
Jimenez, Connie R.
Griffioen, Arjan W.
Nowak-Sliwinska, Patrycja
Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
title Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
title_full Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
title_fullStr Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
title_full_unstemmed Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
title_short Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment
title_sort integrating phenotypic search and phosphoproteomic profiling of active kinases for optimization of drug mixtures for rcc treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564658/
https://www.ncbi.nlm.nih.gov/pubmed/32967224
http://dx.doi.org/10.3390/cancers12092697
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