PubMed · 13994603
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H TSUNEMOTO, T YAMAGAMI. 1963. [Gallbladder shadows with Osbil].. https://pubmed.ncbi.nlm.nih.gov/13994603/
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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.
Electrophilic N-acyloxy-N-alkoxyamides are mutagenic in Salmonella typhimurium TA100 without the need for S9 metabolic activation and they react with DNA at guanine-N7 at physiological pH. Since these are direct-acting mutagens, structural factors influence binding and reactivity with DNA. Mutagenicity in TA100 can be predicted by a QSAR incorporating hydrophobicity (logP), stability to substitution reactions at nitrogen (pK(a) of the leaving acid) and steric effects of para-aryl substituents (E(s)). A number of mutagens exhibit activities that deviate markedly from the predicted values and they fall into two classes: di-tert-butylated N-benzoyloxy-N-benzyloxybenzamides, which--because of their size--are most probably excluded from the major groove or are unable to achieve a transition state for reaction with DNA, and N-benzoyloxy-N-butoxyalkylamides with branching alpha-to the amide carbonyl, which are resistant to S(N)2 reactions at the amide nitrogen.
BACKGROUND: Imatinib mesylate inhibits several tyrosine kinases, including BCR-ABL, the C-KIT receptor, and the platelet-derived growth factor receptors alpha and beta, all of which are associated with disease. We observed that hypophosphatemia developed in some patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who were receiving imatinib. METHODS: We identified 16 patients who had low serum phosphate levels and 8 patients who had normal serum phosphate levels, all of whom were receiving imatinib. We performed the following biochemical measurements: whole-blood levels of ionized calcium, plasma levels of intact parathyroid hormone, and serum levels of total calcium, phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, magnesium, and markers of bone formation (bone alkaline phosphatase and osteocalcin) and bone resorption (N-telopeptide of collagen cross-links); urinalysis; and phosphate, calcium, and creatinine levels in "spot" urine specimens. RESULTS: Patients in the low-phosphate group (median serum phosphate level, 2.0 mg per deciliter [0.6 mmol per liter]; normal level, >2.5 mg per deciliter [0.8 mmol per liter]) had elevated parathyroid hormone levels and low-to-normal serum calcium levels, were younger, and were receiving a higher dose of imatinib than patients in the normal-phosphate group (median level, 3.2 mg per deciliter [1.0 mmol per liter]). Both groups had high levels of phosphate excreted in the urine and markedly decreased serum levels of osteocalcin and N-telopeptide of collagen cross-links. CONCLUSIONS: Hypophosphatemia, with associated changes in bone and mineral metabolism, develops in a proportion of patients taking imatinib for either chronic myelogenous leukemia or gastrointestinal stromal tumors. The drug may inhibit bone remodeling (formation and resorption), even in patients with normal serum phosphate levels.