PURPOSE: Recent clinical trials showed that the sequential combination of epidermal growth factor receptor @entity669 kinase inhibitors ( @entity470 -TKIs) and chemotherapy could prolong the PFS and/or OS of advanced @entity1149 ( @entity1149 ) @entity1 with @entity470 mutation. The aim of present study was to assess the optimal combination sequence and to explore its possible mechanism. METHODS: PC-9 cells and A549 cells, the @entity2220 cells with mutant and wide-type @entity470 respectively, were treated with @entity1205 / @entity4562 alone or in different combination schedules. The @entity470 and @entity984 gene status was determined by qPCR-HRM technique. Cell proliferation was detected by @entity98 assay. The expression and phosphorylation of @entity470 , @entity22166 , @entity584 and @entity2856 were detected by western blot. Cell cycle distribution was observed by flow cytometry. RESULTS: Only sequential administration of @entity1205 followed by @entity4562 ( @entity25986 ) induced significant synergistic effect in both cell lines (Combination Index<0.9). The reverse sequence (G  >  D) resulted in an antagonistic interaction in both cell lines (CI>1.1), whereas the concurrent administration (D+G) showed additive (0.9<CI<1.1)-synergistic effect in PC-9 cells and antagonistic-additive effect in A549 cells. Mechanism studies showed that @entity1205 -induced phosphorylation of @entity470 and @entity22166 was repressed by subsequently used @entity4562 , but not by concurrent exposure of @entity4562 . The @entity4562 -repressed phosphorylation of @entity470 and @entity22166 was reversed neither by concurrent nor by subsequent administration of @entity1205 . D+G reinforced their inhibition on the phosphorylation of @entity2856 in PC-9 cells. CONCLUSIONS: The cytotoxic drugs followed by @entity470 -TKIs may be the optimal combination for antiproliferative effects in @entity470 -mutant @entity1149 cells, and the phosphorylation of @entity470 and @entity22166 might contribute to this effect.

Sequence-dependent antiproliferative effects of @entity4562 and XXXX on @entity1149 ( @entity1149 ) cells and the possible mechanism.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity4562 :: ('MESH:C419708', 'Chemical') :: ['gefitinib'] @entity470 :: ('1956', 'Gene') :: ['EGFR'] @entity984 :: ('3845', 'Gene') :: ['K-ras'] @entity1149 :: ('MESH:D002289', 'Disease') :: ['NSCLC', 'non-small cell lung cancer'] @entity1205 :: ('MESH:C067311', 'Chemical') :: ['docetaxel'] @entity584 :: ('207', 'Gene') :: ['Akt'] @entity22166 :: ('2048', 'Gene') :: ['ERK'] @entity98 :: ('CHEBI:53233', 'Chemical') :: ['MTT'] @entity25986 :: ('p|SUB|D||G', 'ProteinMutation') :: ['D  >  G'] @entity2856 :: ('3480', 'Gene') :: ['IGF-1R'] @entity669 :: ('CHEBI:18186', 'Chemical') :: ['tyrosine'] @entity2220 :: ('MESH:C538231', 'Disease') :: ['lung adenocarcinoma']
@entity1205 :: (MESH:C067311,Chemical) :: ['docetaxel']
