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Open AccessArticle

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

1
Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
2
Comprehensive Cancer Center Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
3
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
4
W.G. (Bill) Hefner Veteran Administration Medical Center, Cancer Center, Salisbury, NC 27157, USA
5
Department of Pulmonary/Critical Care, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
6
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 788; https://doi.org/10.3390/cancers12040788 (registering DOI)
Received: 10 February 2020 / Revised: 13 March 2020 / Accepted: 16 March 2020 / Published: 26 March 2020
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.
Keywords: SCLC; RNA-Seq; patient-derived organoid; thymidylate synthase; fluoropyrimidine SCLC; RNA-Seq; patient-derived organoid; thymidylate synthase; fluoropyrimidine
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Gmeiner, W.H.; Miller, L.D.; Chou, J.W.; Dominijanni, A.; Mutkus, L.; Marini, F.; Ruiz, J.; Dotson, T.; Thomas, K.W.; Parks, G.; Bellinger, C.R. Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10. Cancers 2020, 12, 788.

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