Cancer Letters, Год журнала: 2025, Номер unknown, С. 217668 - 217668
Опубликована: Март 1, 2025
Язык: Английский
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(10), С. 5489 - 5489
Опубликована: Май 17, 2024
Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies peptides, along innovative approaches use of degraders protein interaction inhibitors, which recently demonstrated clinical progress potential in overcoming resistance. Nevertheless, kinase-targeted encounter significant hurdles, including drug resistance, greatly impacts benefits patients, well concerning toxicity when combined immunotherapy, restricts full utilization current treatment modalities. Despite these challenges, development remains highly promising. The extensively studied tyrosine family has 70% its stages development, while 30% inadequately explored. Computational technologies play a vital role accelerating novel repurposing existing drugs. Recent FDA-approved SMKIs underscore importance blood-brain barrier permeability long-term patient benefits. This review provides comprehensive summary recent based mechanisms action targets. We summarize latest developments new explore emerging inhibition from perspective. Lastly, we outline obstacles future prospects inhibition.
Язык: Английский
Процитировано
20
Nature Reviews Drug Discovery, Год журнала: 2025, Номер unknown
Опубликована: Янв. 28, 2025
Язык: Английский
Процитировано
4
The American Journal of Surgical Pathology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 14, 2025
Although sialoblastoma (SBL) is defined as a low-grade malignant salivary gland anlage neoplasm in the 2022 World Health Organization (WHO) Classification of Head and Neck Tumors, its histology, genetics, behavior remain controversial due to rarity tumor. Here, we performed first comprehensive clinical, histologic, molecular analyses 8 SBLs better understand their pathogenesis prognosis. This cohort consisted 5 boys 3 girls, with ages ranging from birth 9 years at diagnosis. Tumors occurred parotid (4), cheek (3), submandibular glands (1). Histologically, tumors primarily presented solid pattern consisting primitive basaloid epithelial cells, often necrosis. Three exhibited non-solid pattern, 1 tumor mainly showing epithelial-myoepithelial carcinoma (EMC)-like whereas other 2 basal cell adenoma (BCA)-like histology. All harbored FGFR2 mutations, also mutations PALB2, AR, MAP2K1. In contrast, were characterized by HRAS or significant β-catenin nuclear positivity. recurred, them developed distant metastases, died 40 44 months after showed no evidence disease recurrence 49, 144, 132 months, suggesting relatively favorable Overall, can be stratified into patterns, usually having increasing risk metastasis. stratification underscores importance genetic morphologic profiling for predicting prognosis SBLs.
Язык: Английский
Процитировано
1
Biomedicines, Год журнала: 2024, Номер 12(5), С. 1117 - 1117
Опубликована: Май 17, 2024
Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement survival outcomes; however, metastatic GC remains a lethal malignancy amongst leading causes cancer-related mortality worldwide. Importantly, ongoing molecular characterisation GCs continues to uncover potentially actionable targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs approximately 3–11% GCs. However, whilst several inhibitors FGFR been clinically tested to-date, there are currently no approved FGFR-directed for GC. In this review, we summarise significance as an therapeutic target GC, examine recent pre-clinical clinical data supporting use small-molecule inhibitors, antibody-based therapies, well novel approaches such proteolysis-targeting chimeras (PROTACs) targeting these tumours, discuss challenges opportunities associated their development.
Язык: Английский
Процитировано
5
BMC Cancer, Год журнала: 2025, Номер 25(1)
Опубликована: Янв. 6, 2025
Ondansetron orally soluble pellicle can serve as an alternative option for preventing nausea and vomiting in patients who receive chemotherapy. However, there is a lack of clinical evidence regarding ondansetron. This study aimed to explore the efficacy safety ondansetron with malignant tumours received chemotherapy drugs moderate-to-high emetic risk. In total, 163 24 mg via pellicles at 30 min before (8 each time three consecutive administrations). The incidence rates days after were recorded. Regarding effect on vomiting, complete response (zero episodes vomiting), major (1–2 minor (3–5 failure (> 5 vomiting) 96.9%, 1.2%, 0%, respectively. rate (complete + rates) was 98.1%. Moreover, 96.3% did not experience nausea, 2.5% experienced mild 1.2% moderate 0.0% severe nausea. (no nausea) 96.3%. Age > 65 years negatively associated regimen involving cisplatin A total 42 (25.8%) adverse events. most common events elevated levels alanine transaminase (6.7%), aspartate (3.7%), fatigue cough (2.5%). shows good antiemetic high
Язык: Английский
Процитировано
0
Annals of Oncology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
0
Опубликована: Янв. 16, 2025
Fibroblast growth factor receptor 2 (FGFR2) is an important member of tyrosine kinase (RTK) family. FGFR2 amplification occurs at a high frequency in gastric cancer (GC) and has been proven to be closely associated with poor prognosis insensitivity chemotherapy or immunotherapy. Current FGFR2-targeted therapies have limited efficacy. Hence, how enhance efficacy reverse resistance are urgent problems clinically. Src homology region 2-containing protein phosphatase (SHP2) serves as the shared downstream mediator all RTKs prominence immunosuppressive molecule. In this study, we identified 6.2% (10/161) GC samples our center. Then showed that dual blocking SHP2 enhanced effects inhibitor (FGFR2i) FGFR2-amplified both vitro vivo via suppressing RAS/ERK PI3K/AKT pathways. We further it overcame FGFR2i by reversing feedback activation mediated other continuously FGFR2-initiated Notably, blockade could suppress PD-1 expression promoted IFN-γ secretion CD8 + T cells, enhancing cytotoxic functions cells tumor immune microenvironment. Overall, findings suggest compelling rationale targeted treatment regulation for GC.
Язык: Английский
Процитировано
0
Опубликована: Янв. 16, 2025
Fibroblast growth factor receptor 2 (FGFR2) is an important member of tyrosine kinase (RTK) family. FGFR2 amplification occurs at a high frequency in gastric cancer (GC) and has been proven to be closely associated with poor prognosis insensitivity chemotherapy or immunotherapy. Current FGFR2-targeted therapies have limited efficacy. Hence, how enhance efficacy reverse resistance are urgent problems clinically. Src homology region 2-containing protein phosphatase (SHP2) serves as the shared downstream mediator all RTKs prominence immunosuppressive molecule. In this study, we identified 6.2% (10/161) GC samples our center. Then showed that dual blocking SHP2 enhanced effects inhibitor (FGFR2i) FGFR2-amplified both vitro vivo via suppressing RAS/ERK PI3K/AKT pathways. We further it overcame FGFR2i by reversing feedback activation mediated other continuously FGFR2-initiated Notably, blockade could suppress PD-1 expression promoted IFN-γ secretion CD8 + T cells, enhancing cytotoxic functions cells tumor immune microenvironment. Overall, findings suggest compelling rationale targeted treatment regulation for GC.
Язык: Английский
Процитировано
0
European Journal of Cancer, Год журнала: 2025, Номер unknown, С. 115262 - 115262
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
0
Journal of Medicinal Chemistry, Год журнала: 2025, Номер 68(3), С. 3886 - 3899
Опубликована: Янв. 31, 2025
Fibroblast growth factor receptors (FGFRs) are established oncogenic drivers in various solid tumors. However, the approved FGFR inhibitors face challenges with acquired resistance and dose-limiting adverse effects associated FGFR1/4 inhibition, limiting therapeutic efficacy. Herein, we systematically explored linker electrophile moieties based on pyrrolopyrazine carboxamide core identified aniline α-fluoroacrylamide as an effective covalent warhead. Compound 10 potently inhibited FGFR2 FGFR3, even context of common inhibitor-resistance mutations, including gatekeeper, molecular brake, activation loop regions. spared other kinases without causing diarrhea serum phosphate elevation vivo. Oral administration compound induced tumor stasis or regression SNU-16 gastric cancer model favorable pharmacokinetics robust pharmacodynamic suppression.
Язык: Английский
Процитировано
0