Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer.

摘要: Members of the human epidermal growth factor receptor (HER) family play a significant role in bladder cancer progression and may underlie development chemotherapy resistance. Dacomitinib is an irreversible tyrosine kinase inhibitor with structural specificity for catalytic domains (EGFR), HER2 HER4 that has exhibited vigorous efficacy against other solid tumors. We evaluated antitumor activity dacomitinib cell lines expressing varying levels HER receptors. These also were established as xenografts nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice to assess vivo. Significant cytotoxic cytostatic effects noted cells elevated target receptors apoptosis cycle arrest being predominant mechanisms Cells lower much less sensitive dacomitinib. Interestingly, was more active than either trastuzumab or cetuximab vitro, increased inhibition tumor compared lapatinib. Pharmacodynamic included decreased E-cadherin (E-cad) expression, reduction EGFR extracellular signal-regulated (ERK) phosphorylation reduced mitotic count. inhibited chemotherapy-resistant xenograft and, when xenograft, superior individual treatments. Evaluation xenograft-bearing revealed this combination broadly feasible well tolerated. In conclusion, pronounced both single agent models. Further investigation preclinical clinical trial settings pursued.