ArticleBMC medical genomics2020
Whole-exome sequencing reveals potential mechanisms of drug resistance to FGFR3-TACC3 targeted therapy and subsequent drug selection: towards a personalized medicine.
Article in BMC medical genomics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 12 citations in OpenAlex.
- Lysine demethylases 6 A and 6B as epigenetic regulators in therapeutic resistance of cancer.Clinical epigenetics · 2025Review
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- Oncogenic gene fusions in cancer: from biology to therapy.Signal transduction and targeted therapy · 2025Review
- Review
- Advances in the study of the role of high-frequency mutant subunits of the SWI/SNF complex in tumors.Frontiers in oncology · 2024Review
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundDrug resistance is a major obstacle to effective cancer therapy. In order to detect the change in tumor genomic states under drug selection pressure, we use next-generation sequencing technology to investigate the underlying potential mechanisms of drug resistance.
methodsIn our study, we presented a bladder cancer patient who had been a bona fide responder to first-line gemcitabine plus cisplatin regimen and second-line pazopanib (tyrosine kinase inhibitor (TKI) for FGFR3-TACC3 fusion) but finally had disease progression as an ideal case for showing genomic alteration during drug resistance. We applied whole-exome sequencing and ultra-deep target sequencing to the patient pre- and post- pazopanib resistance. Protein-protein interaction (PPI) network and Gene Ontology (GO) analyses were used to analysis protein interactions and genomic alterations. Patient-derived xenograft (PDX) model was built to test drug sensitivity.
resultsTwelve mutations scattered in 12 genes were identified by WES pre- pazopanib resistance, while 63 mutations in 50 genes arose post- pazopanib resistance. PPI network showed proteins from multiple epigenetic regulator families were involved post- pazopanib resistance, including subunits of chromatin remodeler SWI/SNF complex ARID1A/1B and SMARCA4, histone acetylation writers CREBBP, histone methylation writer NSD1 and erasers KDM6A/5A. GO enrichment analysis showed pazopanib resistance genes were prominently tagged for chromatin modification, transcription, as well as gland development, leaving genes with the best adaptive FGFR TKI-coping mechanisms. In addition, significantly elevated tumor mutational burden suggested possible utility of immunotherapy. Intriguingly, PDX model suggested that, sensitivity to original chemotherapy regimen (cisplatin) was restored in patient tumor post-pazopanib.
conclusionsEpigenetic regulation may play a role in acquired TKI resistance. Our study traced the complete tumor genomic variation course from chemo-resistant but TKI-sensitive to TKI-resistant but chemo-(re) sensitive, revealing the potential complex dynamic drug-driven mechanisms of resistance.
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