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Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10

Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug...

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Autores principales: Gmeiner, William H., Miller, Lance D., Chou, Jeff W., Dominijanni, Anthony, Mutkus, Lysette, Marini, Frank, Ruiz, Jimmy, Dotson, Travis, Thomas, Karl W., Parks, Graham, Bellinger, Christina R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226016/
https://www.ncbi.nlm.nih.gov/pubmed/32224870
http://dx.doi.org/10.3390/cancers12040788
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author Gmeiner, William H.
Miller, Lance D.
Chou, Jeff W.
Dominijanni, Anthony
Mutkus, Lysette
Marini, Frank
Ruiz, Jimmy
Dotson, Travis
Thomas, Karl W.
Parks, Graham
Bellinger, Christina R.
author_facet Gmeiner, William H.
Miller, Lance D.
Chou, Jeff W.
Dominijanni, Anthony
Mutkus, Lysette
Marini, Frank
Ruiz, Jimmy
Dotson, Travis
Thomas, Karl W.
Parks, Graham
Bellinger, Christina R.
author_sort Gmeiner, William H.
collection PubMed
description Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug target, but conventional TS inhibitors display limited clinical efficacy in refractory or recurrent SCLC. We performed RNA-Seq analysis to identify gene expression changes in SCLC biopsy samples to provide mechanistic insight into the potential utility of targeting pyrimidine biosynthesis to treat SCLC. We identified systematic dysregulation of pyrimidine biosynthesis, including elevated TYMS expression that likely contributes to the lack of efficacy for current TS inhibitors in SCLC. We also identified E2F1-3 upregulation in SCLC as a potential driver of TYMS expression that may contribute to tumor aggressiveness. To test if TS inhibition could be a viable strategy for SCLC treatment, we developed patient-derived organoids (PDOs) from human SCLC biopsy samples and used these to evaluate both conventional fluoropyrimidine drugs (e.g., 5-fluorouracil), platinum-based drugs, and CF10, a novel fluoropyrimidine polymer with enhanced TS inhibition activity. PDOs were relatively resistant to 5-FU and while moderately sensitive to the front-line agent cisplatin, were relatively more sensitive to CF10. Our studies demonstrate dysregulated pyrimidine biosynthesis contributes to drug resistance in SCLC and indicate that a novel approach to target these pathways may improve outcomes.
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spelling pubmed-72260162020-05-18 Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10 Gmeiner, William H. Miller, Lance D. Chou, Jeff W. Dominijanni, Anthony Mutkus, Lysette Marini, Frank Ruiz, Jimmy Dotson, Travis Thomas, Karl W. Parks, Graham Bellinger, Christina R. Cancers (Basel) Article Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug target, but conventional TS inhibitors display limited clinical efficacy in refractory or recurrent SCLC. We performed RNA-Seq analysis to identify gene expression changes in SCLC biopsy samples to provide mechanistic insight into the potential utility of targeting pyrimidine biosynthesis to treat SCLC. We identified systematic dysregulation of pyrimidine biosynthesis, including elevated TYMS expression that likely contributes to the lack of efficacy for current TS inhibitors in SCLC. We also identified E2F1-3 upregulation in SCLC as a potential driver of TYMS expression that may contribute to tumor aggressiveness. To test if TS inhibition could be a viable strategy for SCLC treatment, we developed patient-derived organoids (PDOs) from human SCLC biopsy samples and used these to evaluate both conventional fluoropyrimidine drugs (e.g., 5-fluorouracil), platinum-based drugs, and CF10, a novel fluoropyrimidine polymer with enhanced TS inhibition activity. PDOs were relatively resistant to 5-FU and while moderately sensitive to the front-line agent cisplatin, were relatively more sensitive to CF10. Our studies demonstrate dysregulated pyrimidine biosynthesis contributes to drug resistance in SCLC and indicate that a novel approach to target these pathways may improve outcomes. MDPI 2020-03-26 /pmc/articles/PMC7226016/ /pubmed/32224870 http://dx.doi.org/10.3390/cancers12040788 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
Gmeiner, William H.
Miller, Lance D.
Chou, Jeff W.
Dominijanni, Anthony
Mutkus, Lysette
Marini, Frank
Ruiz, Jimmy
Dotson, Travis
Thomas, Karl W.
Parks, Graham
Bellinger, Christina R.
Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10
title Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10
title_full Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10
title_fullStr Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10
title_full_unstemmed Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10
title_short Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10
title_sort dysregulated pyrimidine biosynthesis contributes to 5-fu resistance in sclc patient-derived organoids but response to a novel polymeric fluoropyrimidine, cf10
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226016/
https://www.ncbi.nlm.nih.gov/pubmed/32224870
http://dx.doi.org/10.3390/cancers12040788
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