The acquisition of resistance to protein kinase inhibitors is a growing problem in @entity5 treatment. We modeled acquired resistance to the @entity16629 (mitogen-activated or extracellular signal-regulated protein kinase kinases 1 and 2) inhibitor @entity17528 ( @entity17528 ) in @entity14 cell lines harboring mutations in @entity817 (COLO205 and HT29 lines) or @entity984 (HCT116 and LoVo lines). @entity17528 -resistant derivatives were refractory to @entity17528 -induced cell cycle arrest and @entity204 and exhibited a marked increase in @entity1366 ( @entity3962 ) pathway signaling and @entity4910 abundance when assessed in the absence of inhibitor. Genomic sequencing revealed no acquired mutations in @entity12363 or @entity29343 , the primary target of @entity17528 . Rather, resistant lines showed a marked up-regulation of their respective driving oncogenes, @entity817 (600E) or @entity984 (13D), due to intrachromosomal amplification. Inhibition of @entity817 reversed resistance to @entity17528 in COLO205 cells, which suggested that combined inhibition of @entity16629 and @entity817 may reduce the likelihood of acquired resistance in @entity5 with @entity817 (600E). Knockdown of @entity984 reversed @entity17528 resistance in HCT116 cells as well as reduced the activation of @entity1366 and @entity25449 ; however, the combined inhibition of @entity1366 and @entity4357 3-kinase signaling had little effect on @entity17528 resistance, suggesting that additional @entity984 effector pathways contribute to this process. Microarray analysis identified increased expression of an 18-gene signature previously identified as reflecting @entity16629 pathway output in resistant cells. Thus, amplification of the driving oncogene ( @entity817 (600E) or @entity984 (13D)) can drive acquired resistance to @entity16629 inhibitors by increasing signaling through the @entity1366 pathway. However, up-regulation of @entity984 (13D) leads to activation of multiple @entity984 effector pathways, underlining the therapeutic challenge posed by @entity984 mutations. These results may have implications for the use of combination therapies.

Amplification of the driving oncogene, XXXX or @entity817 , underpins acquired resistance to @entity16629 inhibitors in @entity14 cells.

@entity5 :: ('MESH:D009369', 'Disease') :: ['tumors', 'cancer'] @entity984 :: ('3845', 'Gene') :: ['KRAS'] @entity3962 :: ('5594;5595', 'Gene') :: ['extracellular signal-regulated kinases 1 and 2'] @entity4910 :: ('595', 'Gene') :: ['cyclin D1'] @entity16629 :: ('5604;5605', 'Gene') :: ['MEK1/2'] @entity25449 :: ('2185', 'Gene') :: ['protein kinase B'] @entity14 :: ('MESH:D015179', 'Disease') :: ['colorectal cancer'] @entity17528 :: ('MESH:C517975', 'Chemical') :: ['selumetinib', 'AZD6244'] @entity817 :: ('673', 'Gene') :: ['BRAF'] @entity204 :: ('MESH:D003643', 'Disease') :: ['death'] @entity29343 :: ('5605', 'Gene') :: ['MEK2'] @entity4357 :: ('MESH:D010716', 'Chemical') :: ['phosphatidylinositol'] @entity1366 :: ('5595;5594', 'Gene') :: ['ERK1/2'] @entity12363 :: ('5604', 'Gene') :: ['MEK1']
@entity984 :: (3845,Gene) :: ['KRAS']
