Abstract
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.
Highlights
Small cell lung cancer (SCLC) is a highly lethal lung cancer sub-type with a median survival of only 15–20 months [1]
Unlike NSCLC for which some patients respond to receptor tyrosine kinase (RTK) inhibitors [5], SCLC is not characterized by a reliance on RTK-mediated signaling
Our studies provide new insights into how dysregulated expression of genes important for nucleoside metabolism contribute to the lack of efficacy for conventional fluoropyrimidine drugs (5-FU, capecitabine) in SCLC treatment
Summary
Small cell lung cancer (SCLC) is a highly lethal lung cancer sub-type with a median survival of only 15–20 months [1]. The majority of SCLC patients present with extensive disease for which the 5-year survival rate is only 2% [2]. Chemotherapy (e.g., cisplatin/carboplatin+etoposide) remains central to SCLC treatment and while highly effective at inducing an initial remission, relapse is nearly inevitable and recurrent disease is unresponsive to further therapy [3,4]. There are no small molecule targeted therapies for SCLC treatment. High TS activity may indicate SCLC cells are dependent on the de novo nucleotide biosynthetic pathway and may be vulnerable to TS inhibitors such as 5-FU [10], tomudex [11], and pemetrexed [12]. Clinical studies with these agents have not demonstrated strong efficacy in SCLC [10,11,12]
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