CTPS1 inhibition suppresses proliferation and migration in colorectal cancer cells

Wu, Fahong; Mao, Yudong; Ma, Tao; Wang, Xiaoli; Wei, Hangzhi; Wang, Tianwei; Wang, Jia; Zhang, Youcheng

doi:10.1080/15384101.2022.2105084

Cited by 9 publications

(9 citation statements)

References 41 publications

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“…In keeping with the latter, several recent preclinical papers have described a role for CTPS1 in cancer, and highlighted selective CTPS1 inhibition as a potential antitumor target. [12][13][14] Key to unlocking CTPS1 as a cancer target was the development of a chemical series with selectivity for CTPS1 over CTPS2. A combination of site-directed mutagenesis and interspecies comparisons identified the isoleucine 250 residue of CTPS1 as critical to the selectivity of the compound series described herein.…”

Section: Discussionmentioning

confidence: 99%

CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma

Asnagli

Minet

Pfeiffer³

et al. 2023

HemaSphere

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Lymphoma is the most common hematological malignancy and is among the 10 most prevalent cancers worldwide. Although survival has been improved by modern immunochemotherapeutic regimens, there remains a significant need for novel targeted agents to treat both B-cell and T-cell malignancies. Cytidine triphosphate synthase 1 (CTPS1), which catalyzes the rate-limiting step in pyrimidine synthesis, plays an essential and nonredundant role in B-cell and T-cell proliferation but is complemented by the homologous CTPS2 isoform outside the hemopoietic system. This report describes the identification and characterization of CTPS1 as a novel target in B- and T-cell cancers. A series of small molecules have been developed which show potent and highly selective inhibition of CTPS1. Site-directed mutagenesis studies identified the adenosine triphosphate pocket of CTPS1 as the binding site for this small molecule series. In preclinical studies, a potent and highly selective small molecule inhibitor of CTPS1 blocked the in vitro proliferation of human neoplastic cells, showing the highest potency against lymphoid neoplasms. Importantly, pharmacological CTPS1 inhibition induced cell death by apoptosis in the majority of lymphoid cell lines tested, thus demonstrating a cytotoxic mechanism of action. Selective CTPS1 inhibition also inhibited the growth of neoplastic human B- and T- cells in vivo. These findings identify CTPS1 as a novel therapeutic target in lymphoid malignancy. A compound from this series is in phase 1/2 clinical studies for the treatment of relapsed/refractory B- and T-cell lymphoma (NCT05463263).

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Section: Discussionmentioning

confidence: 99%

CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma

Asnagli

Minet

Pfeiffer³

et al. 2023

HemaSphere

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“…Numerous studies have reported that CTP synthase activity is often increased in proliferating cells and cancers. 16,[25][26][27][28][29][30] CTPS1 can be significantly up-regulated by T-cell activation via the ERK pathway, which is required for rapid T-cell proliferation, precise control of acute EBV infection and the survival and outgrowth of EBV-positive B cells. 16,24 In this study, we showed that cytidine metabolism reprogramming plays a key role in MCL cell survival and drug resistance, at least in part, by interacting with dsDNA-cGas-STING pathway.…”

Section: Discussionmentioning

confidence: 99%

“…CTP synthase is an important nucleotide metabolism enzyme involved in metabolism reprogramming. Numerous studies have reported that CTP synthase activity is often increased in proliferating cells and cancers 16,25–30 . CTPS1 can be significantly up‐regulated by T‐cell activation via the ERK pathway, which is required for rapid T‐cell proliferation, precise control of acute EBV infection and the survival and outgrowth of EBV‐positive B cells 16,24 .…”

Section: Discussionmentioning

confidence: 99%

“…We classified MCL patients into two groups using a nucleotide metabolism‐related prognostic model we established, which revealed that different activities of nucleotide metabolism are associated with distinct downstream transcriptional pathways and clinical outcomes. CTPS1, as the most vital one among the six selected predictive genes, has been reported to be involved in the development of various solid tumours 28,29 and MYC overexpressing cancers 27,30 . We therefore tested the effects of CTPS1, CTPS2 and DHODH on MCL cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…Growth curves analysis was performed at 96 h post-sgRNA expression and 48 hours postpuromycin selection. most vital one among the six selected predictive genes, has been reported to be involved in the development of various solid tumours 28,29 and MYC overexpressing cancers. 27,30 We therefore tested the effects of CTPS1, CTPS2 and DHODH on MCL cell growth.…”

Section: F I G U R Ementioning

confidence: 99%

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MYC‐induced cytidine metabolism regulates survival and drug resistance via cGas‐STING pathway in mantle cell lymphoma

Liang

Ren

et al. 2023

Br J Haematol

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Metabolic reprogramming, a hallmark of cancers, plays a fundamental role in tumourigenesis and tumour progression by facilitating the uptake and utilization of essential nutrients from the environment to maintain cell viability and a high proliferation rate in tumour cells. [1][2][3][4][5] Additionally, metabolic reprogramming has been observed in the development of haematological malignancies and is considered as a potential therapeutic target against cancer metabolism. 6 However, little is known regarding the role of metabolic reprogramming in the progression and drug resistance of mantle cell lymphoma (MCL), a subtype of B-cell lymphoma that accounts for 6%-8% of non-Hodgkin's lymphoma. 7,8 Our preliminary data indicated that nucleotides are the most crucial metabolites in MCL cell lines, with the de novo

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