TYMS expression

NEK2 is highly expressed in ESCC and can promote the migration, proliferation and invasion of ESCC cells. NEK2 mediates ESCC immunotherapy.

The correlation between the expression of HMGB1, HMGB2, and their targets was analyzed in PCa patient samples and also in PCa subgroups, classified as neuroendocrine positive or negative, in public databases. These results allow a better understanding of the role of HMGB proteins in PCa and contribute to find specific biomarkers for aggressive PCa.

Our analysis indicates variations in metabolism among different breast cancer subtypes and sampling locations which details the heterogeneity of the breast tumours. Correlation analysis of [18 F]FDG tracer uptake, transcriptome and tumour metabolites like acetate and serine facilitate the search for new candidates for metabolic tracers and permit distinguishing luminal A and B. This knowledge may help to differentiate subtypes preclinically or to provide patients guide for neoadjuvant therapy and optimised surgical protocols based on individual tumour metabolism.

The most commonly used chemotherapy for colorectal cancer (CRC) is the application of 5-fluorouracil (5-FU)...This study also shows that NaB inhibits the migration of CRC cells and can cause cell cycle arrest in the G2/M phase. These results suggest that NaB could be developed as a potential therapeutic adjuvant to improve the therapeutic effect of 5-FU in CRC.

Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

EPE components reduced TYMS expression by occupation of SP1 motifs on the tyms promoter and reversed the EMT phenotype of invasive MPM cells. Further in-depth analysis of the molecular docking of polyphenol compounds with SP1 regulatory motifs is required.

Our study indicated a novel and effective regulatory capacity of TYMS in the cell proliferation of ESCC by relieving oxidative stress through activating expression of Nrf2 and Nrf2-dependent antioxidant enzymes genes. These properties make TYMS and Nrf2 as appealing targets for ESCC clinical chemotherapy.

Our results indicate the potential benefit of genome-edited iPS cells based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.

When we treated high and low PNP expressing CLL B-cells from untreated patients with drugs known to be active in CLL, interestingly we found high PNP expressing CLL B-cells are sensitive to Bcl2 inhibitor venetoclax and AXL kinase inhibitor TP-0903 versus low PNP expressing CLL B-cells...However treatment of CLL B-cells from untreated patients cultured alone or co-cultured with BMSCs with TYMS inhibitor raltitrexed did not show any killing indicating an alternate role of TYMS in BMSC cultured CLL B-cells...In conclusion, these results indicate that active purine and pyrimidine metabolism in CLL B-cells augmented by the BM environment can support CLL B-cell survival and drug resistance and possible induction of EMT components. Future studies are underway to understand the role and regulation of PNP and TYMS in CLL disease progression and drug resistance for both untreated and treated CLL patients.

RET-rearranged tumors obtained from females, but not males, had a decreased level of expression of thymidylate synthase (p < 0.00001), which is a known predictive marker of the efficacy of pemetrexed. The results of our study provide a viable alternative for RET testing in facilities that do not have access to NGS due to cost or technical limitations.

The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based (5-FU-based) regimens is an important factor in the mortality of metastatic CRC (mCRC)...In this manuscript, we review mechanisms of 5-FU resistance with an emphasis on: (1) altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate (5-Fluoro-2'-deoxyuridine-5'-O-monophosphate; FdUMP); (2) elevated expression or activity of the primary enzymatic target thymidylate synthase (TS); and (3) dysregulated programmed cell death as important causes of 5-FU resistance. Importantly, these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine (FP) polymers (e.g., CF10) that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.

While using 5-FU-based regimens such as FOLFOX and FOLFIRI in combination with biologics confer a survival benefit, their ineffectiveness at promoting long-term survival in a substantial fraction of mCRC patients and associated toxicities limits their use...Our findings suggest the significance of elevated TS in CRC metastatic progression and 5-FU resistance and demonstrate that CF10 may be effective at inhibiting CRC metastatic progression. CF10 may be a successful candidate for early-phase clinical trials to treat mCRC.

Mechanistically, we confirm the compound and its analogues are a multifunctional non-classical antifolate, and we identify structural features allowing direct TYMS inhibition while also maintaining the ability to inhibit dihydrofolate reductase (DHFR). Collectively, this work identifies new non-classical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile highlighting potential for enhanced cancer therapy.

5-Fluorouracil (5-FU) is currently being used to treat a wide range of cancers, including breast, pancreatic, head and neck, colorectal, ovarian, and gastric cancers The objective of this study was to establish a new methodology for the low-cost, one-pot synthesis of uracil derivatives (UD-1 to UD-5) and to evaluate their therapeutic potential in BC cells...Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro. In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of thymidylate synthase.

Decreased TS protein expression can be indicative of greater responsivness to pemtrexed and of longer TTP and OS in individuals with advanced MPM (locally progressed or metastatic) who are receiving pemetrexed-based chemotheraphy. Low ERCC1 expressions in individuals with advanced MPM can predict increased PFS and OS, as well as a better responsivness to platinum-based chemotherapy. In patients with progressed MPM receiving gemcitabine plus cisplatin chemotherapy, lower RRM1 expression was associated with a better prognosis, longer PFS, and longer OS.

Some colorectal cancer (CRC) patients are resistant to 5-fluorouracil (5-FU), and high expression levels of thymidylate synthase (TS) contribute to this resistance...Also, quercetin suppressed TS and PCNA protein expression in the distal colon tissue of CRC mice. These results suggest that quercetin has the potential to be used as an adjuvant with 5-FU for the treatment of CRC.

More importantly, we also demonstrated that the EPE decreases the cell invasiveness of 5-fluorouracil (5-FU) resistant CRC cells...Our results indicate that the EPE might be an effective anticancer agent in suppressing colon cancer metastasis regardless of the invasiveness cause. Based on these findings, we concluded that the used EPE extract rich in polyphenols inhibits cell invasion by TYMS downregulation.

In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1 mutant background. This work will re-focus attention on new strategies to inhibit TS activity for PanNET treatment.

ALK-positive patients experience clinical benefit from pemetrexed-based chemotherapy possibly due to lower thymidylate synthase (TS) levels...D5F3 and 5A4 clones have the highest percentage of agreement. TS levels are significantly lower in FISH-positive patients.

Thymidylate synthase (TYMS) is the crucial enzymatic precursor for DNA biosynthesis and, therefore, the critical target for numerous types of chemotherapy, including the most frequently applied agent in colon cancer treatment 5-fluorouracil (5-FU)...Overall, our study showed a correlation between TYMS level and invasion ability in colon cancer cells and, above all, a crucial role of TYMS in the EMT regulation. We postulate that chemotherapeutics that decrease or inhibit TYMS expression could increase the effectiveness of the therapy in patients with colon cancer, especially in the metastatic stage.

MSI GC was associated with high TS levels, which may explain therapeutic resistance to 5-FU. Additionally, MSI + TS-high showed better survival, but without improvement with CMT.

Our results provide evidence that cinobufagin might be a potential agent for the treatment of cancers such as hepatocellular carcinoma. It can also promote the scientific development of Chansu, and has great significance for enriching the application of TCM in the development of new anti-tumor drugs.

The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS)...A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM.

Our findings suggest that TYMS-TM4SF4 axis may promote the progression of CRC by EMT and upregulating stem cell markers.

Silenced TYMS, the downstream target gene of miR-140-3p, reversed the effects of miR-140-3p downregulation on TYMS expression, cell viability, colony formation, migration, invasion, and tube length as well as the metastasis-, apoptosis- and angiogenesis-related proteins in LUAD cells. Upregulation of miR-140-3p inhibited the proliferation, migration, invasion and angiogenesis of LUAD cells via targeting TYMS.

Moreover, resveratrol could significantly alleviate the visfatin effect on capecitabine-treated CRC cells. These results provided new insights to understand the capecitabine susceptibility of CRC under a visfatin-containing environment and a possible therapeutic application of resveratrol in CRC patients with obesity.

Combination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint.

Low nanomolar doses of the FLT3 inhibitor (FLT3i) AC220 and an inhibition of class I HDACs with nanomolar concentrations of FK228 or micromolar doses of the HDAC3 specific agent RGFP966 synergistically induce apoptosis of AML cells that carry hyperactive FLT3 with an internal tandem duplication (FLT3-ITD). A genetic depletion of HDAC3 attenuates the expression of such proteins. Thus, class I HDACs and hyperactive FLT3 appear to be valid targets in AML cells with mutant FLT3.

The microRNA-330 inhibited cell proliferation by suppressing thymidylate synthase (TYMS) in colorectal cancer. Therefore, suggesting that they are valuable factors for further studies of alternative treatment and diagnostic methods.

The results of chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays suggested that H3K27 acetylation in the 5'-UTR of TYMS may promote its expression in drug-resistant cells. Our findings indicate that the intracellular levels of dTMP are potential biomarkers for the effective treatment of patients with MPM and suggest the importance of regulatory mechanisms of TYMS expression in the disease.

A significant positive correlation was observed between AEG-1, TS, ERCC1, EGFR, and VEGF gene expression levels in CRC cell lines, and low AEG-1 and TS expression were highly sensitive to 5-fluorouracil treatment...In multivariate Cox regression analysis, high AEG-1 expression could be an independent prognostic factor indicating poor survival in patients with resectable stage III CRC treated with adjuvant chemotherapy. In conclusion, AEG-1 expression and tumor grade are potential prognostic factors for recurrence and survival in patients with stage III CRC receiving adjuvant fluoropyrimidine-based chemotherapy.

Erlotinib, afatinib, and osimertinib interacted with GZ17-6.02 to kill NSCLC cells expressing mutant EGFR proteins. The drug combination reduced the expression of HDAC2 and HDAC3, which correlated with lower PD-L1, IDO1, and ODC levels and increased MHCA expression. Collectively, our data support consideration of combining GZ17-6.02 and pemetrexed in osimertinib-resistant NSCLC.

Approximately 65% of 5-FU was released at the highest amplitude and exposure time was investigated. The results are encouraging for the stimulated and controlled release of 5-FU for the management of colorectal cancer.

TGF-βRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

We performed additional mechanistic analyses to redefine neratinib biology and determined the mechanisms by which the multi-kinase inhibitor neratinib interacted with the thymidylate synthase inhibitor pemetrexed to kill NSCLC cells expressing either mutant KRAS (G12S; Q61H; G12A; G12C) or mutant NRAS (Q61K) or mutant ERBB1 (L858R; L858R T790M; exon 19 deletion)...Afatinib or osimertinib resistant cells were killed with a similar efficacy to non-resistant cells...Thus, neratinib targets an unidentified protein whose functional inhibition directly results in RAS inactivation and tumor cell killing. Our data prove that, albeit indirectly, oncogenic RAS proteins are druggable by neratinib.

Funding: Isofol Medical AB Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene...In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin...MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy . Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC . MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.

Colon cancer patients with MSI show resistance to 5-Fluorouracil (5-FU) but sensitivity to immunosuppressive checkpoint inhibitors (ICIs)...The substitutions and location of somatic mutations in different genes were at variance between MSS and MSI patients. In conclusion, our research determined mechanisms of MSI associated treatment response, and may provide potential value for improving the survival of colon cancer patients.

Background - 5-fluorouracil (5-FU) in combination with the folate leucovorin (LV) has formed the backbone of chemotherapy for advanced colorectal cancer for several decades...We previously reported that high tumoral expression of genes involved in folate transport, polyglutamation, and metabolism was associated with decreased risk of recurrent disease in patients with stage III colorectal cancer treated with 5-FU + LV (FLV) alone, or in combination with oxaliplatin (FLOX) according to the Nordic bolus regimen. The aim of the present study was to determine the association between expression of the folate-associated genes ABCC3, MTHFD2, SLC19A1, SLC25A32, SLC46A1, and TYMS and outcome of patients with metastatic colorectal cancer subjected to palliative chemotherapy.Patients and Methods - A total of 290 patients treated with FLV (n = 113), FLOX (n = 102) or FLV + irinotecan (FLIRI, n = 75) were included...Multivariate models showed that low TYMS and high SLC25A32 expression in subgroup 1 and high ABCC3 expression in subgroup 2 correlated significantly with better PFS (Hazard Ratio (HR) = 0.75 (95% CI = 0.57-1.0), HR = 2.21 (95% CI = 1.37-3.6), and HR = 1.34 (95% CI = 1.08 -1.7), respectively).Conclusion - Expression of TYMS, the target enzyme of 5-FU, was strongly associated with clinical benefit in the whole group, whereas expression of TYMS and the folate transporters SLC25A32, and ABCC3 was associated with PFS in the subgroups (stage I-III and stage IV), respectively. The prospective global phase III study AGENT is presently conducted on patients with advanced colorectal cancer, to determine whether expression of these genes can predict response to 5-FU-based chemotherapy that includes LV or the novel folate arfolitixorin.

The knockdown of ANT2 or PHB2 promoted proteasomal degradation of TS protein, whereas that of not ANT2 but PHB2 reduced TS mRNA levels. Thus, our study reveals the ANT2- and PHB2-mediated pleiotropic regulation of TS expression and demonstrates the possibility of rabdosianone I as a lead compound of TS suppressor.

We found that fTME, with the enrichment of NK cells, may predict the lack of postoperative CT/RCT efficacy in stage Ib/II GC, which may be associated with hypoxia and TS expression. Further validations and mechanism researches are needed.