PubMed · 1492825
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S Ewart. Moclobemide.. https://pubmed.ncbi.nlm.nih.gov/1492825/
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BACKGROUND: Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a critical bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. METHODS: We integrated large-scale pharmacogenomic profiling of the FGFR inhibitor AZD4547 from the GDSC2 and PRISM databases with single-cell RNA sequencing to dissect the multi-omics landscape of FGFRi resistance across 312 cell lines from 8 cancer types. This multi-omics framework was further extended by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. In vitro viability assays and western blot analysis were subsequently conducted to experimentally evaluate the predicted FGFR-EGFR synthetic lethality. RESULTS: Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1, highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell analysis unveiled that resistance is linked to the heterogeneous enrichment of baseline subpopulations characterized by distinct metaprograms, including cell-cycle dysregulation. Furthermore, a random forest model built on a LASSO-derived transcriptomic signature was constructed, demonstrating promising predictive capability for AZD4547 sensitivity (mean test-set AUC = 0.73, 95% CI [0.63, 0.80]); the signature generalized well to erdafitinib but showed limited transferability to some other FGFR inhibitors (e.g. pemigatinib, BGJ398). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing converging computational evidence for EGFR pathway activation as an adaptive bypass mechanism. This predicted synthetic lethality was experimentally supported in two FGFR-dependent cell line models (RT112 and CCLP1), in which combined FGFR-EGFR inhibition produced marked synergistic antiproliferative effects. CONCLUSIONS: This study establishes a comprehensive multi-omics atlas of resistance to the FGFR inhibitor AZD4547, delineating convergent mechanisms of metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize the resistance as a dynamic network rewiring and nominate rational combination strategies to overcome this therapeutic bottleneck. While FGFR-EGFR co-inhibition is experimentally supported, metabolic co-targeting remains a computationally derived, hypothesis-generating strategy.
Poly (ADP-ribose) polymerase is a cellular repair enzyme synthesised following damage to DNA. 3-Aminobenzamide (3-AB) is an inhibitor of this repair enzyme. To study repair efficiency in leprosy patients, who usually show a significantly higher frequency of spontaneous chromosome aberrations and sister-chromatid exchanges (SCEs), their blood lymphocyte cultures were treated with 3-AB. A marginal increase in the frequency of chromosome aberrations was observed following treatment with 3-AB in controls as well as in patient groups. There was also no significant difference in the frequency of SCEs in control cultures with or without 3-AB. A significant increase in the frequency of SCEs was observed in lymphocyte cultures of paucibacillary (PB) and multibacillary (MB) patients treated with 3-AB when compared with controls. Observation of a significant increase in the frequency of SCEs in 3-AB-treated cultures over the untreated value indicates that DNA damage caused in leprosy patients following mycobacterial infection is not repaired because of the presence of the inhibitor of repair enzyme.
Gastrin has been postulated to be a physiological growth factor, but compelling in vitro evidence of this has been difficult to obtain. In the present study we investigated whether small cell lung carcinoma cell lines could provide a useful model system to study the effects of gastrin on signal transduction and cell proliferation in vitro. We found that the addition of gastrin to small cell lung cancer cells loaded with the fluorescent Ca2+ indicator fura 2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. The [Ca2+]i response was especially prominent in the small cell lung carcinoma cell line H510. In this cell line, gastrin I, gastrin II, cholecystokinin residues 26-33 (CCK-8), and unsulfated CCK-8 increased [Ca2+]i in a concentration-dependent fashion with half-maximum effects at 7, 2.5, 3, and 5 nM, respectively. The Ca(2+)-mobilizing effects of gastrin and CCK-8 were prevented by proglumide, benzotript, and the specific gastrin/CCKB receptor antagonist L365260. Gastrin stimulated the clonal growth of H510 cells in semisolid (agarose-containing) medium, increasing both the number and the size of the colonies. Gastrin and CCK agonists were equally effective in promoting clonal growth. The broad-spectrum neuropeptide antagonists [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P and [Arg6,D-Trp7,9,MePhe8] substance P (6-11) markedly inhibited gastrin-stimulated Ca2+ mobilization and clonal growth. These results show that gastrin acts as a direct growth factor through gastrin/CCKB receptors and demonstrate, for the first time, that these peptides can stimulate the proliferation of cells outside the gastrointestinal tract.