Fibroblast growth factor receptors (FGFRs) are recognized therapeutic targets in cancer. We here describe insights underpinning the impact of mutations on FGFR1 and FGFR3 kinase activity and drug efficacy, using a combination of computational calculations and experimental approaches including cellular studies, X-ray crystallography and biophysical and biochemical measurements. Our findings reveal that some of the tested compounds, in particular TKI258, could provide therapeutic opportunity not only for patients with primary alterations in but also for acquired resistance due to the gatekeeper mutation. The accuracy of the computational methodologies applied here shows a potential for their wider application in studies of drug binding and in assessments of functional and mechanistic impacts of mutations, thus assisting efforts in precision medicine.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471147 | PMC |
| http://dx.doi.org/10.1016/j.ebiom.2015.02.009 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex.
Proc Natl Acad Sci U S A
February 2025
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510050, China.
Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models.
View Article and Find Full Text PDFActivation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages.
Proc Natl Acad Sci U S A
February 2025
Department of Biological Sciences, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202.
The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear.
View Article and Find Full Text PDFComputational analysis of the effect of a binding protein (RbpA) on the dynamics of Mycobacterium tuberculosis RNA polymerase assembly.
PLoS One
January 2025
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India.
Background: RNA polymerase-binding protein A (RbpA) is an actinomycetes-specific protein crucial for the growth and survival of the pathogen Mycobacterium tuberculosis. Its role is essential and influences the transcription and antibiotic responses. However, the regulatory mechanisms underlying RbpA-mediated transcription remain unknown.
View Article and Find Full Text PDFGenome-wide DNA methylation and transcriptome sequencing analyses of lens tissue in an age-related mouse cataract model.
PLoS One
January 2025
Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang, China.
DNA methylation is known to be associated with cataracts. In this study, we used a mouse model and performed DNA methylation and transcriptome sequencing analyses to find epigenetic indicators for age-related cataracts (ARC). Anterior lens capsule membrane tissues from young and aged mice were analyzed by MethylRAD-seq to detect the genome-wide methylation of extracted DNA.
View Article and Find Full Text PDFProteomics Reveals Mechanisms of Delayed Keratoconus Progression: A Study of Corneas Following Two Light-Activated Crosslinking Treatments.
Invest Ophthalmol Vis Sci
January 2025
University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands.
Purpose: This study aims to elucidate on changes in biological pathways in rabbit corneas induced by two methods of light-activated corneal stiffening: topical application of riboflavin with dextran (RF-D) or WST11 with dextran (WST-D) followed by ultraviolet A (UVA) or near-infrared (NIR) illumination, respectively.
Methods: Rabbit corneas were mechanically de-epithelialized, then left untreated (N = 3) or treated with either RF-D/UVA (N = 3) or WST-D/NIR (N = 3). After one week, quantitative proteomics was performed on untreated, RF-D/UVA- and WST-D/NIR-treated corneas.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!