PMCID string | Title string | Sentences string |
|---|---|---|
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Western blotting analysis revealed that HDM201 treatment elevated p53 and p21 levels in p53 WT cells, whereas adavosertib modulated Wee1 and phospho-cdc2 expression in both p53 WT and p53 MT cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430 and GIST882 cells were inoculated subcutaneously into NOD/SCID mice and treated with HDM201 (100 mg/kg, two times per week) or adavosertib (50 mg/kg, five times per week). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Compared to the control group, GIST430 tumor volume and weight were significantly decreased in the HDM201 group (Fig. 5A–C). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Moreover, GIST882 tumors exhibited a size reduction, although no significant difference was observed in tumor volume and weight between the adavosertib and control groups (Fig. 5D–F). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 treatment led to a significant reduction in the tumor volume and weight of p53 WT GIST cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In contrast, p53 MT tumors exhibited a moderate decrease in size after adavosertib treatment. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Body weight was monitored throughout the treatment period, and no significant changes were observed (Fig. 5G,H). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This study investigated the therapeutic potential of MDM2 and Wee1 inhibitors (HDM201 and adavosertib, respectively) in GIST, with a focus on their p53 dependency. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The p53 tumor suppressor protein is mutated in the majority of human cancers, with mutation rates varying according to cancer type . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | When the TP53 gene undergoes mutation, it can either lose its normal tumor-suppressive function or gain new oncogenic properties. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Consequently, mutant p53 cell lines offer a more faithful representation of actual tumor behavior in cancer research. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Certain p53 mutations, such as R175H, R248Q, and R273H, increase cancer cell aggressiveness, promote rapid proliferation, and may even alter cellular metabolism . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | As a result, mutant p53 cell models are pivotal for investigating the oncogenic role of p53 and for developing novel therapies aimed at targeting these mutant variants [34–36]. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The GIST cell lines GIST48, GIST430, GIST882, and GIST-T1 are widely used as experimental models for GIST, thanks to their well-characterized mutation sites in the KIT gene . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Among these four lines, GIST882 and GIST-T1 harbor mutant p53, featuring deletions in p53 exon 1 and exons 2–7, respectively . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This study maintains GIST430 (p53 WT), GIST882, and GIST-T1 (p53 MT), which can serve as experimental models in GIST preclinical testing for developing potential therapeutics targeting p53 or related pathways. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | All three cell lines carry KIT mutations. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430 carries a primary KIT exon 11 mutation (p.V560_L576del) and a secondary resistance mutation (p.V654A), making it imatinib-resistant. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST882 harbors a KIT exon 13 mutation (p.K642E), and GIST-T1 has a KIT exon 11 mutation (p.V560_Y578del); both are considered imatinib-sensitive . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430 was derived from a GIST that progressed during imatinib mesylate (IM) therapy, thereby conferring IM resistance . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST882 was established from an untreated human GIST and remains sensitive to IM . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST-T1, also from an untreated human, is highly sensitive to IM at low nanomolar doses . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Although IM exhibits strong anti-proliferative effects, it often fails to induce sufficient apoptosis, resulting in low pathologic complete remission rates and a high rate of secondary progression in metastatic settings . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These genetic backgrounds reflect clinically relevant KIT mutation subtypes and provide a representative spectrum for investigating therapeutic responses in GIST models. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Consequently, more effective treatment is needed. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | While the overall incidence of TP53 mutations in GIST is relatively low (3.5%), they are more commonly observed in gastric GISTs, which are associated with poorer recurrence-free survival (RFS) . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Accordingly, this study employed both wild-type and mutant p53 GIST models to examine how p53 dysfunction influences GIST biology and to assess its effect on the efficacy of p53-targeted therapies, laying the groundwork for future clinical research. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The study’s findings indicated that HDM201 effectively inhibited cell growth and induced apoptosis in GIST cells harboring wild-type p53. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In addition, adavosertib predominantly induced apoptosis in p53 MT GIST cells, but not in p53 WT cells, suggesting a p53-dependent therapeutic response (Fig. 6). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These findings are consistent with those of previous studies that reported the antitumor effects of MDM2 inhibitors, including nutlin-3 in osteosarcoma , nutlin-3a in leukemia and neuroblastoma , and HDM201 in melanoma and liver adenocarcinoma . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Notably, to the best of our knowledge, this is the first in vivo study to investigate the therapeutic potential of MDM2 inhibitors in GIST. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Furthermore, adavosertib treatment led to a significant increase in caspase-3/7 activity and a higher percentage of cells in the sub-G1 phase, as well as both early and late apoptosis in p53 MT GIST cells (GIST882 and GIST-T1) (Figs. 2 and 3). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These findings are consistent with those of previous studies that reported that adavosertib significantly upregulates apoptosis markers, including γ-H2AX and cleaved PARP, in p53 MT cells , supporting its apoptotic effect in p53-mutant GIST models. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In contrast, the study’s data indicated that adavosertib primarily induced G2/M arrest, with only moderate growth inhibition and no substantial apoptosis, in p53 WT GIST430 cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This is likely because of the requirement for cell cycle regulation in response to replication stress following G1/S checkpoint deficiency in combination with Wee1 inhibition . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Following the DNA damage response (DDR), p53 WT cells typically undergo cell cycle arrest at the G1 checkpoint to allow for DNA repair before replication. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In contrast, p53 MT cells predominantly rely on the G2 checkpoint for DNA repair . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In this study, adavosertib induced S or G2/M phase arrest in p53 MT GIST cells (Fig. 2A,B), consistent with previous reports that elucidated its role in inducing S/G2/M arrest in p53 MT biliary tract cancer, gastric cancer, GIST, and anaplastic thyroid carcinoma (ATC) . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Previously, Bukhari et al. (2019) reported that Wee1 inhibition in osteosarcoma cells disrupts mitotic progression, leading to frequent centromere fragmentation and mitotic catastrophe . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Similarly, our findings suggest that Wee1 inhibition in p53 MT GIST cells induces DNA content shifts, disrupts cell cycle progression, results in cell cycle arrest at the S or G2/M phases, and ultimately triggers apoptosis. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The western blot analysis revealed that adavosertib treatment disrupted cell cycle control in p53 MT GIST cells, leading to increased Wee1 phosphorylation (p-Wee1) and reduced phospho-cdc2 (p-cdc2) expression. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The decrease in p-cdc2 suggests the impairment of the cdc2-cyclin complex, which is indicative of DNA damage. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Although our results showed an initial upregulation of p-Wee1 following adavosertib treatment, Rajeshkumar et al. reported that this effect was transient . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Notably, Wee1 undergoes sequential phosphorylation, leading to its degradation via the ubiquitin-proteasome pathway, which ultimately activates cdc2, promotes mitotic entry, and results in replication stress accumulation . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Our results suggest that p53-mutant GIST cells may exhibit increased reliance on the G2/M checkpoint, rendering them more vulnerable to Wee1 inhibition. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These findings highlight how both KIT and p53 genetic contexts influence drug responsiveness and may inform future combination strategies or biomarker-guided therapeutic approaches. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Although adavosertib efficacy is partially hindered by the presence of functional p53 in p53 WT cells, HDM201 exhibits strong p53-dependent antitumor activity. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Our results confirm that HDM201 effectively induces growth inhibition and apoptosis in p53 WT GIST cells by stabilizing p53 and upregulating its downstream targets, while showing limited efficacy in p53 MT cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These findings align with the in vitro results of a previous study that reported that another MDM2 inhibitor, nutlin-3, effectively induced apoptosis in p53 WT GIST cell lines . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Unlike tyrosine kinase inhibitors (e.g., imatinib, sunitinib, regorafenib, and ripretinib), which primarily exert cytostatic effects , our results showed that HDM201 has the potential to induce apoptosis specifically in p53 WT GIST cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, the lack of histopathological examination is a limitation of our current study. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In future experiments, we plan to incorporate histopathological evaluations at early time points to verify the on-target effects of our interventions. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Specifically, we will increase the number of mice to allow tumor collection at 24 and 48 h following the first and second administration of the inhibitor, enabling us to analyze key protein expression levels, including p53-related proteins (e.g., p21), cell cycle-related proteins (e.g., cdc2), and apoptosis-related proteins (e.g., PARP). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Additionally, to assess immune cell infiltration, we will use C57BL/6J (B6) mice for an in vivo study, perform H&E staining, and collect tumors for FACS analysis of T cell markers such as CD4 and CD8 . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These analyses will provide a better correlation between on-target effects and our observed outcomes, further elucidating how HDM201 and adavosertib regulate the cell cycle, induce apoptosis, and exert anti-tumor effects based on p53 status. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Despite the promising preclinical data supporting the use of MDM2 inhibitors in GIST, clinical studies targeting p53 in GIST are currently lacking . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Furthermore, to date, no clinical trials have investigated p53-targeted therapies in patients with GISTs. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Given the lack of effective MDM2 inhibitors in clinical practice, further studies are required to explore the therapeutic feasibility of targeting the p53 pathway in GIST. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Nevertheless, our results suggest that targeting the p53 pathway may be a potential therapeutic strategy. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Importantly, determining the p53 status in patients could facilitate personalized treatment strategies. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In low-risk GIST patients, surgical resection is feasible. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, for high-risk and metastatic GIST, we propose a treatment strategy that incorporates p53-targeted therapy into KIT/PDGFRA inhibitor regimens to overcome drug resistance. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | For high-risk GIST, KIT/PDGFRA inhibitors such as imatinib, sunitinib, regorafenib, and ripretinib could be administered as neoadjuvant therapy to reduce tumor size and stage, followed by surgery and p53-targeted adjuvant therapy to eliminate residual cancer cells and lower recurrence risk. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | For metastatic GIST, which may not be amenable to surgery, a sequential approach using KIT/PDGFRA inhibitors followed by p53-targeted inhibitors or a combination of both from the outset could be considered . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In this context, patients with p53 WT tumors may benefit from an MDM2 inhibitor combined with a KIT/PDGFRA inhibitor, while those with p53 MT tumors might respond more favorably to a Wee1 inhibitor combined with a KIT/PDGFRA inhibitor, thus further enhancing response rates. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Specifically, GIST430 cells, which retain wild-type p53 and are imatinib-resistant , were selected as the primary model for combination treatment with HDM201 to investigate p53-dependent mechanisms under clinically relevant resistance conditions. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In addition, future studies may explore the combination of adavosertib and sunitinib using GIST882 and GIST-T1 cells, both of which harbor mutant p53 and are sensitive to sunitinib , to evaluate synergistic effects in distinct genetic contexts. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Moreover, to assessment of p53 status in clinical settings remains technically challenging due to both tumor heterogeneity and limitations in current detection methods. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | While techniques such as RNA sequencing and digital PCR offer high sensitivity for detecting TP53 mutations , their clinical applicability may be limited by cost, turnaround time, and the need for high-quality nucleic acid samples. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In routine clinical practice, p53 status is often inferred through immunohistochemistry (IHC), which is cost-effective and widely available, but may lack the precision to distinguish between different mutation subtypes or functional consequences. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In addition, intra-tumoral heterogeneity can complicate interpretation, especially in the context of sub-clonal mutations or differential expression in metastatic vs. primary lesions. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | To address these challenges, future approaches may combine multiple modalities, such as next-generation sequencing (NGS) panels with digital PCR validation and IHC for functional protein assessment to achieve a more comprehensive and clinically actionable evaluation of p53 status. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The development of liquid biopsy-based assays (such as circulating tumor DNA) may also offer a non-invasive method to monitor TP53 mutations over time and across tumor sites, potentially improving real-time therapeutic decision-making . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Regarding the specific TP53 mutations in the GIST882 and GIST-T1 cell lines, we mentioned that GIST882 carries a TP53 exon 1 deletion, and GIST-T1 harbors a larger homozygous deletion spanning exons 2–7 previously . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Both mutations lead to loss-of-function alterations, resulting in a p53-null phenotype with complete loss of p53 transcriptional activity (Fig. 4), rather than missense or nonsense mutations that might confer dominant-negative or gain-of-function effects. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | We acknowledge that the current study does not deeply explore the functional consequences of different TP53 mutation subtypes on the efficacy of adavosertib. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This represents a limitation, as varying TP53 mutation types could influence therapeutic responses differently, particularly in cases with retained or neomorphic p53 function. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Concerning in vivo validation, our study included in vivo testing with adavosertib as a single agent therapy in the GIST882 model, which demonstrated efficacy in p53-null cell lines. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, we did not perform in vitro and in vivo experiments evaluating combination therapies. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This is a notable limitation, as combining adavosertib with other targeted therapies (such as KIT inhibitors) could potentially enhance efficacy or overcome resistance mechanisms in GIST, particularly in the context of TP53 mutations. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Future studies should prioritize in vivo validation of combination therapies using GIST models with diverse TP53 mutation profiles to better elucidate synergistic effects and differential sensitivities. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This study’s findings highlight the distinct therapeutic responses to HDM201 and adavosertib according to p53 status, underscoring the significance of p53 as a biomarker for guiding treatment selection in GIST. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, because this combination strategy has yet to be evaluated in a preclinical setting, further research is needed to establish a foundation for clinical trials. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Moreover, to further overcome resistance, combination therapy with TKIs and other agents may improve treatment efficacy. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Resistance to HDM201 may arise from MDM2 amplification or overexpression, which could enhance p53 degradation in TP53 wild-type cells , though this is less relevant in p53-null models like GIST882 and GIST-T1. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Additionally, mutations in downstream p53 signaling pathways (such as p21 or BAX) could diminish HDM201 efficacy. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | For adavosertib, resistance may stem from compensatory activation of alternative DNA damage response pathways, such as ATR/Chk1 signaling, or upregulation of other G2/M checkpoint regulators . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In GIST, KIT secondary mutations could also contribute to resistance by sustaining oncogenic signaling despite Wee1 inhibition. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 and adavosertib could complement existing GIST therapies, particularly for patients with imatinib-resistant tumors driven by KIT secondary mutations or TP53 alterations. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 use in TP53 wild-type GISTs, where MDM2 inhibition can restore p53 function, potentially synergizing with tyrosine kinase inhibitors (TKIs) like imatinib or sunitinib. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Adavosertib, effective in p53-null models, could be integrated as a second or third-line therapy for imatinib-refractory cases, particularly in combination with TKIs to target both KIT-driven proliferation and DNA damage response vulnerabilities. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In addition, novel targets are under investigation example, CDK1 has been identified as a key regulator of GIST growth and proliferation, suggesting that CDK1 inhibitors could be potential therapeutic agents . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Immunotherapeutic strategies, such as combining immune checkpoint inhibitors with anti-angiogenic agents, have shown promise in GIST treatment . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Furthermore, many new drugs are currently in clinical trials for advanced GISTs, with some already entering phase III trials, including targeting PDGFRα/β, VEGFR, or GTPase . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These agents show promising efficacy and safety profiles, but more clinical data are needed to fully confirm their benefits. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This study revealed that HDM201 exerts potent p53-dependent antitumor effects by inducing apoptosis in p53 WT GIST cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In contrast, adavosertib promoted G2/M arrest and apoptosis primarily in p53 MT GIST cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In vivo studies further validated the efficacy of HDM201 in reducing the tumor burden in p53 WT GIST430 xenografts, whereas adavosertib showed modest effects in p53 MT GIST882 models. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These findings provide a strong rationale for the development of tailored therapeutic strategies targeting the p53 pathway in GIST. |
PMC11502962 | Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape | The infiltration of immune cells and their roles of the infiltrating-immune cells in gastrointestinal stromal tumor (GIST) is still unclear. |
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