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WEE1 and PKMYT1 biological functions. a Schematic representation of WEE1 and PKMYT1 involvement in cell cycle checkpoints. WEE1 regulates the activity of both CDK1 and CDK2 kinases (trough phosphorylation of Tyr15) and is involved in the regulation of intra-S, G2/M, and M phase cell cycle checkpoints. PKMYT1 selectively regulates CDK1 (through phosphorylation of Tyr15 and Thr14) and is plays a role in the G2/M phase checkpoint. b Schematic representation of the regulation of MUS81-EME1/2 endonuclease complexes by WEE1 during S and G2/M cell cycle phases. By inhibiting CDK2 or CDK1, WEE1 prevents MUS81 activation and the generation of DNA damages during S phase, and chromosomes pulverization during G2/M phase
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The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and canc...
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Simple Summary
A major theory of cancer development is that cancer originates from a specialised type of tumour cell called the cancer stem cell (CSC). Although CSCs comprise a relative subpopulation to the overall heterogeneous tumour mass, they are responsible for cancer establishment, progression, metastasis, and relapse. The eradication of CSCs...
Citations
... WEE1 is a tyrosine kinase that functions through inhibition of both CDK1 and CDK2 activity by phosphorylation at tyrosine 15 (Y15). It is involved in several stages of cell cycle regulation, including intra-S, G2/M and M (23). Additionally, WEE1 regulates the G1/S cell cycle transition and protects stalled replication forks through inhibiting CDK2 activity (24,25). ...
... Compared with control cells, DNA fibers in OV90 Cyclin E1 cells were shorter, indicating Cyclin E1 overexpression alone increased baseline replication stress. Azenosertib treatment reduced the length of DNA fibers in both cell lines ( Fig. 2D; Supplementary Fig. S2F), supporting previous reports that WEE1 inhibition resulted in replication stress (23). The significantly shorter length of DNA fibers in OV90 Cyclin E1 cells compared to control cells suggests a model wherein azenosertib treatment exacerbates existing replication stress beyond threshold levels, ultimately leading to cell death. ...
Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell-cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms. Finally, we provided early evidence from an ongoing phase I study demonstrating clinical activity of monotherapy azenosertib in patients with Cyclin E1/CDK2 activated ovarian and uterine serous carcinomas.
... An additional gene implicated in human bladder cancer, the tumor suppressor WEE1, is located in the disease associated chr21:31405230-33951574 region. WEE1 regulates the G2/M checkpoint through an activation loop with cell division kinases, CDK1 and CDK2, within the MAPK signaling pathway 56,57 . Activating BRAF mutations, which are found in the majority of canine iUC tumors, increase cellular levels of WEE1 protein 58 . ...
... This mutation is in the N-terminal regulatory domain of WEE1, adjacent to the nuclear export signal and is predicted to affect the function of the gene. In humans bladder urothelial carcinomas WEE1 is frequently dysregulated through copy number loss (13.7%) 57 . ...
Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12–22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs.
... Similarly, a combination of PARPi with WEE1 inhibitors has exhibited encouraging results in a recent phase II study [98]. WEE1 is a kinase that regulates the cell cycle by inhibiting CDK1 in response to DNA damage, thereby preventing DNA replication [99]. When WEE1 is inhibited, the cell cycle progresses without checkpoints, leading to DNA damage accumulation and cell death [99]. ...
... WEE1 is a kinase that regulates the cell cycle by inhibiting CDK1 in response to DNA damage, thereby preventing DNA replication [99]. When WEE1 is inhibited, the cell cycle progresses without checkpoints, leading to DNA damage accumulation and cell death [99]. The WEE1 inhibitor adavosertib was evaluated alone or in combination with olaparib in 80 patients with PARPi-resistant OC [98]. ...
Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments.
... [63,64] DNA damage-inducing agents such as oxaliplatin, taxol, and radiotherapy, which have been used clinically for treating tumors, can induce mitotic errors and CIN; [5,10,47,65] while SAC activator, such as MK-1775 and ZN-c3, are in clinical trials and are considered as potential anti-tumor drugs. [66] Meanwhile, increasing evidences suggest that a population of tumor cells remain viable after exposure to various anti-tumor drugs. These residual cells display reduced drug sensitivity, thereby providing a reservoir of cells that might seed the growth of drug-resistant recurrent tumor. ...
Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well‐recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly understood. Here, using a cross‐omics approach, YY2 is identified as a mitotic regulator that promotes SAC activity by activating the transcription of budding uninhibited by benzimidazole 3 (BUB3), a component of SAC. While both conditions induce CIN, a defect in YY2/SAC activity enhances mitosis and tumor growth. Meanwhile, hyperactivation of SAC mediated by YY2/BUB3 triggers a delay in mitosis and suppresses growth. Furthermore, it is revealed that YY2/BUB3‐mediated excessive CIN causes higher cell death rates and drug sensitivity, whereas residual tumor cells that survived DNA damage‐based therapy have moderate CIN and increased drug resistance. These results provide insights into the role of SAC activity and CIN levels in influencing tumor cell survival and drug response, as well as suggest a novel anti‐tumor therapeutic strategy that combines SAC activity modulators and DNA‐damage agents.
... Pre-clinical data support the efficacy of adavosertib in combination with chemotherapy, which has subsequently been investigated in multiple clinical trials (28). Likewise, LB-100 has been proposed as a sensitizer for chemotherapy (14) and is currently under clinical investigation in such combination (NCT04560972). ...
Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance.
Significance
A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.
... As expected, RO-3306 significantly blocked γH2AX and ssDNA induction (Fig. 1i). Together, these data suggest that HT enhanced DNA replication stress and abrogate the G2/M cell cycle checkpoint in a CDK1dependent manner, indicating a potential synergistic effect with WEE1 inhibitors which might further augment CDK1 activity 40 . ...
Hyperthermic intraperitoneal chemotherapy’s role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.
... PDE2A, TEF and DNAJC12 genes. It is reported that GNG12 [27], WEE1 [28], TEF [29] and DNAJC12 [30] participate in cell cycle regulation, cell proliferation and cell apoptosis. PDPN [31], FNDC3B [32], TGIF1 [33] and DNAJC12 [30] are involved in cell migration and metastasis. ...
Background
Increasing evidence have elucidated that PBX3 played a crucial role in cancer initiation and progression. PBX3 was differentially expressed in many cancer types. However, PBX3 potential involvement in gliomas remains to be explored.
Methods
The expression level of PBX3 in glioma tissues and glioma cells, and its correlation with clinical features were analyzed by data from TCGA, GEPIA, CGGA and CCLE. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival. We also analyzed the correlation between PBX3 expression level and survival outcome and survival time of LGG and GBM patients by using linear regression equation. GSEA was used to generate an ordered list of all genes related to PBX3 expression and screening of genes co-expressed with PBX3 mRNA by "limma" package.
Results
The results showed that PBX3 was highly expressed in gliomas and its expression increased with the increase of malignancy. Survival analysis found that PBX3 is more valuable in predicting the OS and PFI of LGG patients than that of GBM. For further study, TCGA and CGGA data were downloaded for univariate Cox analysis and multivariate Cox analysis which showed that the expression of PBX3 was independent influencing factors for poor prognosis of LGG patients. Meanwhile, Receiver operating characteristic (ROC) curve showed that PBX3 was a predictor of overall survival rate and progression-free survival rate of LGG. Linear regression model analysis indicated that the higher expression of PBX3 the higher the risk of death of LGG patients, and the higher expression of PBX3 the higher the risk of disease progression of LGG patients. Next, TCGA data were downloaded for GSEA and Co-expression analyses, which was performed to study the function of PBX3 .
Conclusion
PBX3 may be involved in the occurrence and development of glioma, and has potential reference value for the early diagnosis and prediction of prognosis of glioma.
... Thus, compared to normal cells, these cancers could be particularly susceptible to G2/M checkpoint-targeted therapies, such as WEE1 or CHK1 inhibitors. Inhibition of WEE1 or CHK1 abrogates the G2/ M checkpoint and forces cells to enter mitosis prematurely with unrepaired DNA, ultimately leading to mitotic catastrophe and apoptosis [4,5]. ...
WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.
... WEE1 inhibitors, emerging as a promising targeted therapeutic approach, have been the focus of extensive attention in recent years. WEE1 kinase, the critical regulator of the G2/M cell cycle checkpoint and replication stress response [13], chiefly modulates cell cycle protein-dependent kinase 1, thus facilitating the re-entry of the cell cycle after DNA repair, ultimately ensuring proper cell cycle progression [14]. Correspondingly, inhibiting WEE1 kinase activity leads to a significant amount of unrepaired damaged DNA entering the cell cycle, triggering mitotic catastrophe, and subsequently, tumor cell apoptosis. ...
... DNA damage repair (DDR) molecules, integral to tumor progression, recognize and initiate repair pathways in response to substantial DNA damage [26]. Notably, cell cycle checkpoints, especially WEE1 kinase, play a crucial role in DNA repair processes [13]. Endometrial cancer cell lines HEC-1-B and ISHIKAWA were subcutaneously inoculated into NCG mice. ...
Introduction: Recurrence signifies the primary mortality factor in patients suffering from endometrial cancer, with few efficacious treatments currently available for recurrent cases. This research investigates the anti-tumoral capacities of WEE1 inhibitors within the context of endometrial cancer, aiming to establish a novel therapeutic avenue for high recurrence-risk patients.
Materials and methods: We evaluated WEE1 expression in endometrial cancer patients utilizing immunohistochemistry on paraffin-embedded tissue sections. The cytotoxic potential of WEE1 inhibitors on endometrial cancer cells was assessed by CCK8 assay. Assays to gauge the influence of WEE1 inhibitors on cell proliferation and migration included clonal proliferation, wound healing, and transwell assays. We determined the impacts on apoptosis and cell cycle stages by flow cytometry. Employing qRT-PCR and western blotting, we investigated the mechanistic pathways underlying the anti-tumoral activity of WEE1 inhibitors. In vivo evaluations were executed to ascertain the inhibitory effect of WEE1 inhibitors on tumor growth in mice.
Results: WEE1 exhibited high-level expression in endometrial cancer tissues, particularly pronounced in recurrent compared with non-recurrent patients. WEE1 inhibitors effectively eliminated endometrial cancer cells while inhibiting their proliferation and migration. Flow cytometric analyses revealed a significant promotion of apoptosis and an increase in G2/M phase cell proportion upon WEE1 inhibitor treatment. qRT-PCR and western blotting elucidated that WEE1 inhibitors activated the innate immune signaling pathway in endometrial cancer cells. Furthermore, in vivo assessments demonstrated substantial tumor growth suppression due to WEE1 inhibitors.
Conclusions: WEE1 inhibitors initiated an innate immune response in endometrial cancer, exhibiting considerable anti-tumoral effects, which was promising for postoperative treatment of endometrial cancer, especially recurrent endometrial cancer patients.
... PKMYT1 encodes a member of the serine/threonine protein kinase family, a key regulator of cell cycle, and an integral part of DNA damage repair (DDR)-related signaling [54]. Foreseeably, perturbations in cell cycle correlate with an accumulating progression of DNA damages and trigger apoptosis [55]. Recent studies have suggested that PKMYT1 can potentially activate the Notch signaling pathway, implying a possible range of immune functions [56]. ...
The primary influencer of aquaculture quality in Amphioctopus fangsiao is pathogen infection. Both lipopolysaccharides (LPS) and polyinosinic:polycytidylic acid (Poly I:C) are recognized by the pattern recognition receptor (PRR) within immune cells, a system that frequently serves to emulate pathogen invasion. Hemolymph, which functions as a transport mechanism for immune cells, offers vital transcriptome information when A. fangsiao is exposed to pathogens, thereby contributing to our comprehension of the species’ immune biological mechanisms. In this study, we conducted analyses of transcript profiles under the influence of LPS and Poly I:C within a 24 h period. Concurrently, we developed a Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules and genes. Further, we carried out Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to investigate the primary modular functions. Co-expression network analyses unveiled a series of immune response processes following pathogen stress, identifying several key modules and hub genes, including PKMYT1 and NAMPT. The invaluable genetic resources provided by our results aid our understanding of the immune response in A. fangsiao hemolymph and will further our exploration of the molecular mechanisms of pathogen infection in mollusks.
