scholarly journals Characterization of reactive intermediates formation in dacomitinib metabolism and bioactivation pathways elucidation by LC-MS/MS: in vitro phase I metabolic investigation

RSC Advances ◽  
2018 ◽  
Vol 8 (68) ◽  
pp. 38733-38744 ◽  
Author(s):  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Ali S. Abdelhameed
Keyword(s):  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Reactive Intermediates ◽  
First Line ◽  
Metabolic Investigation ◽  
Epidermal Growth ◽  
Egfr Tkis ◽  
Irreversible Tyrosine Kinase Inhibitor

Dacomitinib (DCB) is a second generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance developed by the first line epidermal growth factor receptor (EGFR) TKIs.

Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma

2020 ◽  
Vol 41 (9) ◽  
pp. 1195-1202
Author(s):  
Yankang Li ◽  
Nasha Zhang ◽  
Li Zhang ◽  
Yemei Song ◽  
Jie Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Nucleotide Polymorphisms ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is effective for most advanced non-small-cell lung cancer (NSCLC) patients with mutant EGFR, some patients show little or no response. Germline variations, such as single-nucleotide polymorphisms (SNPs), have been proved to be involved in disease progression after EGFR-TKI therapy. In this study, we hypothesized that the functional HSPH1 SNP may affect gene expression and, thus, prognosis of NSCLC patients treated with EGFR-TKIs. We systematically examined impacts of HSPH1 SNPs on NSCLC survival in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The promoter rs2280059 polymorphism was significantly associated with patient survival in both cohorts. In vitro and In vivo assays elucidated that rs2280059 G allele shows higher capability to drive HSPH1 promoter activities. Silencing HSPH1 significantly increases the antineoplastic effects of gefitinib on NSCLC cells. Our findings demonstrated potential implications of HSPH1 in clinic, which may lead to better understanding and outcome assessment of EGFR-TKI treatment.

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