BACKGROUND: Identification of early molecular pathway changes may be useful as biomarkers for @entity5 response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor ( @entity7423 ) has been implicated in various aspects of @entity652 development and @entity3 . We show here that, in @entity19 intestinal @entity652 acutely exposed to a small molecular inhibitor of @entity12841 ( @entity4562 ), there is concurrent suppression of @entity12841 downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of @entity12841 signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of @entity7423 using @entity70319 , a small molecular @entity669 kinase inhibitor of @entity7423 . METHODS: Male Apc(min/+) @entity19 with an @entity5 burden were exposed to a single dose of an inhibitor against @entity12841 ( @entity4562 ), @entity7423 ( @entity70319 ), 0.5% @entity9266 or combined @entity12841 / @entity7423 inhibitor and culled 4   h post dosing. @entity5 tissue was analysed to detect the early molecular pathways induced and anti- @entity5 phenotypic changes. Cohorts of male Apc(min/+) @entity19 (n=15-17) were subsequently treated with @entity4562 for a period of 8 weeks and subsequently exposed to single (either @entity4562 or @entity70319 ) or combined ( @entity4562 and @entity70319 ) therapy. We also included a vehicle-treated cohort, which was never exposed to @entity4562 and became symptomatic of the disease by day 150. RESULTS: Both single treatments delayed the onset of disease symptoms. Combined dosing with @entity4562 and @entity70319 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal @entity652 volume (47   mm(3) (comb) vs 248   mm(3) ( @entity70319 ), P=0.0003 and 47   mm(3) (comb) vs 123   mm(3) ( @entity4562 ), P=0.0042, Mann-Whitney (two-sided) test). CONCLUSION: Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo.

Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal XXXX burden in the Apc(min/+) @entity19 .

@entity4562 :: ('MESH:C419708', 'Chemical') :: ['gefitinib'] @entity12841 :: ('13649(Tax:10090)', 'Gene') :: ['EGFR'] @entity5 :: ('MESH:D009369', 'Disease') :: ['intestinal tumour', 'Tumour', 'tumour'] @entity19 :: ('10090', 'Species') :: ['mice', 'murine'] @entity70319 :: ('MESH:C562081', 'Chemical') :: ['AZ12253801'] @entity7423 :: ('16001(Tax:10090)', 'Gene') :: ['IGF1R'] @entity9266 :: ('MESH:D011136', 'Chemical') :: ['Tween 80'] @entity3 :: ('MESH:D009362', 'Disease') :: ['metastasis'] @entity652 :: ('MESH:D000236', 'Disease') :: ['adenomas', 'adenoma'] @entity669 :: ('CHEBI:18186', 'Chemical') :: ['tyrosine']
@entity652 :: (MESH:D000236,Disease) :: ['adenoma']
