A5093781988- Fibroblast Growth Factor Research
- Eosinophilic Disorders and Syndromes
- Epigenetics and DNA Methylation
- Kruppel-like factors research
Ondine Biopharma (United States)
2024
Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These can include fusions, amplifications, rearrangements, mutations. Acquired drug resistance to current FGFR inhibitors often results disease progression unfavorable outcomes for patients. Genomic profiling tumors refractory the clinic has revealed several acquired driver that could be target next generation therapeutics. Herein, we describe how...
FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. alterations are most prevalent intrahepatic cholangiocarcinoma (ICC) bladder cancers, respectively, multiple selective reversible covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved these contexts. However, resistance, due to acquired secondary mutations the FGFR2/3 domain, limits efficacy. Resistance is typically polyclonal, involving a...
<div>AbstractPurpose:<p>FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 alterations are most prevalent intrahepatic cholangiocarcinoma (ICC) bladder cancers, respectively, multiple selective reversible covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved these contexts. However, resistance, due to acquired secondary mutations the FGFR2/3 domain, limits efficacy. Resistance is...
<div>AbstractPurpose:<p>FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 alterations are most prevalent intrahepatic cholangiocarcinoma (ICC) bladder cancers, respectively, multiple selective reversible covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved these contexts. However, resistance, due to acquired secondary mutations the FGFR2/3 domain, limits efficacy. Resistance is...
<p>Supplementary Figure S1. KIN-3248 activity against C492F mutation</p>
<p>Supplementary Figure S2. A. Cell viability assays were conducted to assess IC50 measurements in FGFR3S249C UM-UC-14 parental cells (left) and wild-type, mock-transfected (right) when treated with specific FGFR inhibitors. B-C. curves for carrying N540K (B) or V555M (C) kinase domain mutations their response KIN-3248 other designated inhibitors.</p>
<p>Supplementary Figure S3. Treatment with KIN-3248 is well-tolerated when administered orally at doses up to 15 mg/kg daily. Data are from the CCLP-1 model engineered FGFR2-PHGDH fusion (n=8 mice/group) and presented as mean ± SEM.</p>
<p>Supplementary Figure S1. KIN-3248 activity against C492F mutation</p>
<p>Supplementary Figure S2. A. Cell viability assays were conducted to assess IC50 measurements in FGFR3S249C UM-UC-14 parental cells (left) and wild-type, mock-transfected (right) when treated with specific FGFR inhibitors. B-C. curves for carrying N540K (B) or V555M (C) kinase domain mutations their response KIN-3248 other designated inhibitors.</p>
<p>Supplementary Figure S4. KIN-3248 efficacy is potentiated by MEK inhibitor treatment. Mice bearing the ICC-21 CDX model were treated daily with vehicle, trametinib 0.1 mg/kg, 5 15 mg/kg or combination. A. Serial measurements of tumor volume. n = 8 mice per group. Two-way ANOVA multiple comparisons Tukey correction used to analyze data. ****, P < 0.0001. Data are shown as mean ± SD. B. MSD analysis phosphoERK was performed after last dose (3-days treatment) at indicated timepoints...
<p>Supplementary Figure S3. Treatment with KIN-3248 is well-tolerated when administered orally at doses up to 15 mg/kg daily. Data are from the CCLP-1 model engineered FGFR2-PHGDH fusion (n=8 mice/group) and presented as mean ± SEM.</p>
<p>Supplementary Figure S4. KIN-3248 efficacy is potentiated by MEK inhibitor treatment. Mice bearing the ICC-21 CDX model were treated daily with vehicle, trametinib 0.1 mg/kg, 5 15 mg/kg or combination. A. Serial measurements of tumor volume. n = 8 mice per group. Two-way ANOVA multiple comparisons Tukey correction used to analyze data. ****, P < 0.0001. Data are shown as mean ± SD. B. MSD analysis phosphoERK was performed after last dose (3-days treatment) at indicated timepoints...