UNASSIGNED: 253 Background: @entity1 epidermal receptors (HER) are overexpressed and HER signaling is biologically relevant in @entity150 and may mediate chemotherapy resistance. @entity38871 is a novel, potent, irreversible pan-HER inhibitor with activity against several solid @entity5 , currently in a phase III clinical trial in NSCLC. We hypothesized that @entity38871 has antitumor activity in @entity150 models. METHODS: Expression level of @entity12841 and @entity7171 protein was measured semi-quantitatively in 8 @entity150 cell lines. We treated @entity1 , UM-UC-6, UM-UC-9 cell lines with @entity38871 (1nM-10uM) for 24-72 hours, and measured cell viability, proliferation, apoptosis, and cell cycle effects. Correlations between dose and cell viability were measured by two-way ANOVA (GraphPad Prism 5.0). We injected age-matched male NOD/ @entity915 @entity19 SC with 1x10(6) UM-UC-6 and UM-UC-9 cells, respectively, generating xenografts. @entity19 were randomized and treated with @entity38871 , 6mg/kg p.o. daily, starting 1 day or 1 week after cell injection; controls were treated with vehicle. @entity19 were monitored daily, weighed weekly, sacrificed at 4 weeks and @entity5 weighed. RESULTS: In vitro, significant cytostatic effect was noted with as low as 50nM in UM-UC6 cells and 100nM in UM-UC9 cells. @entity1 cells did not exhibit cytostatic effect even with 1000nM, corresponding to differential target protein (HER) expression. @entity38871 (2uM) induced apoptosis (UM-UC-6), and G1 cell cycle arrest in both cell lines. These effects corresponded to @entity38871 -mediated inhibition of @entity12841 , @entity13436 , AKT phosphorylation. In vivo, xenograft weights in both cell lines were significantly lower in @entity38871 -treated @entity19 vs control (p<0.001), corresponding to pharmacodynamic effects (decreased @entity3112 , p- @entity12841 , p- @entity13436 , mitotic count). @entity38871 6mg/kg p.o. daily resulted in significantly lower @entity5 weights vs @entity9433 50 mg/kg p.o. daily in UM-UC-9 xenograft model (p=0.0052). CONCLUSIONS: @entity38871 demonstrated single-agent activity in @entity150 cell lines and xenografts. Induction of apoptosis and G1 phase arrest are the suggested mechanisms for anti- @entity5 activity. Further investigation of this inhibitor in @entity150 models is being pursued.

Evaluation of a  novel irreversible pan-HER inhibitor in XXXX models.

@entity1 :: ('9606', 'Species') :: ['UM-UC3', 'UM-UC-3', 'Human'] @entity12841 :: ('13649(Tax:10090)', 'Gene') :: ['EGFR'] @entity38871 :: ('MESH:C525726', 'Chemical') :: ['dacomitinib', 'Dacomitinib'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'tumors'] @entity19 :: ('10090', 'Species') :: ['mice', 'Mice'] @entity9433 :: ('MESH:C490728', 'Chemical') :: ['lapatinib'] @entity915 :: ('MESH:D053632', 'Disease') :: ['SCID'] @entity150 :: ('MESH:D001749', 'Disease') :: ['bladder cancer'] @entity13436 :: ('26413(Tax:10090)', 'Gene') :: ['ERK'] @entity7171 :: ('13866(Tax:10090)', 'Gene') :: ['HER2'] @entity3112 :: ('12550(Tax:10090)', 'Gene') :: ['E-cadherin']
@entity150 :: (MESH:D001749,Disease) :: ['bladder cancer']
