The AXL receptor tyrosine kinase is involved in signal transduction in malignant cells. Recent studies have shown that the AXL upregulation underlies epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant non-small cell lung cancer (NSCLC). In this study, we investigated the effect of DS-1205b, a novel and selective inhibitor of AXL, on tumor growth and resistance to EGFR TKIs. In AXL-overexpressing NIH3T3 cells, DS-1205b potently inhibited hGAS6 ligand-induced migration
in vitro
and exerted significant antitumor activity
in vivo
. AXL was upregulated by long-term erlotinib or osimertinib treatment in HCC827 EGFR-mutant NSCLC cells, and DS-1205b treatment in combination with osimertinib or erlotinib effectively inhibited signaling downstream of EGFR in a cell-based assay. In an HCC827 EGFR-mutant NSCLC xenograft mouse model, combination treatment with DS-1205b and erlotinib significantly delayed the onset of tumor resistance compared to erlotinib monotherapy, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors. DS-1205b also delayed the onset of resistance when used in combination with osimertinib in the model. These findings strongly suggest that DS-1205b can prolong the therapeutic benefit of EGFR TKIs in nonclinical as well as clinical settings.
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
1. Pharmacokinetic properties of difloxacin have been studied in pig and chicken after intravenous and oral administration. 2. The serum concentrations of difloxacin in pig and chicken after intravenous administration were best described by a two-compartment open model, giving distribution half-lives of 0.50 and 0.66 h and elimination half-lives of 7.92 and 4.10 h for pig and chicken respectively. The steady-state distribution volumes were 1.70 and 3.06 l/kg for pig and chicken respectively. 3. After oral administration of 5 mg/kg to pig and chicken, the serum concentrations reached maximal levels of 3.61 and 0.96 microg/ml respectively at 1.25 and 1.40 h. The elimination half-lives were 11.8 and 7.35 h for pig and chicken respectively. 4. The bioavailabilities of difloxacin were calculated as 93.7 (pig) and 86.9% (chicken).
Methods: Human BC tissue sections and tissue array were used to ascertain the clinical relevance of Angiomotin-p130 expressing in tumor cells and the formation of VM. We utilized MCF7 and MD-MBA-231 human tumor cells to observe VM in an orthotopic BC model and bevacizumab (anti-VEGF) was used to identify the resistance mechanism of antiangiogenic therapies in breast cancer. Later, tube formation assay was used to explore the efficacy of bevacizumab and anlotinib (anti-VEGFR,PDGFR,FGFR and c-Kit) in the inhibition of VM.Results: According to human datasets and histological analysis Angiomotin-p130 was identified as a bonafide candidate to regulation VM formation through in vitro and in vivo experiments. Stable overexpression of Angiomotin-p130 in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. We identified highly downregulated Angiomotin-p130 in human breast tumor cells and AAT-treated orthotopic mammary tumors. AAT-treated (bevacizumab and anlotinib) tumors displayed a higher number of Angiomotin-p130-negative tumor cells than endothelial-like phenotypes. Tube formation assay showed that the bevacizumab and anlotinib had no significant difference in inhibition on VM, though anlotinib inhibited the proliferation of tumor cells.
Conclusions:The present study suggests that tumor cell autonomous Angiomotin-p130 pathway may play an important role in AAT-mediated resistance and VM formation in BC. Therefore, targeting Angiomotin-p130 can be combined with standard antiangiogenic therapies to improve the therapeutic outcomes in clinical trials.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.