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author:("ema, lung")
1.  Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression, decreased BAK activation, and not by ERBB receptor mutation 
Molecular pharmacology  2008;74(3):807-822.
We have defined some of the mechanisms by which the kinase inhibitor Lapatinib kills HCT116 cells. Lapatinib inhibited radiation-induced activation of ERBB1/2, ERK1/2 and AKT, and radiosensitized HCT116 cells. Prolonged incubation of HCT116 cells with Lapatinib caused cell killing followed by outgrowth of Lapatinib adapted cells. Adapted cells were resistant to serum-starvation –induced cell killing and were cross resistant to multiple therapeutic drugs. Lapatinib was competent to inhibit basal and EGF-stimulated ERBB1 phosphorylation in adapted cells. Co-expression of dominant negative ERBB1 and dominant negative ERBB2 inhibited basal and EGF-stimulated ERBB1 and ERBB2 phosphorylation in parental cells. However in neither parental nor adapted cells did expression of dominant negative ERBB1 and dominant negative ERBB2 recapitulate the cell death promoting effects of Lapatinib. Adapted cells had increased expression of MCL-1, decreased expression of BAX, and decreased activation of BAX and BAK. Over-expression of BCL-XL protected parental cells from Lapatinib toxicity. Knock down of MCL-1 expression enhanced Lapatinib toxicity in adapted cells that was reverted by knock down of BAK expression. Inhibition of caspase function modestly reduced Lapatinib toxicity in parental cells whereas knock down of AIF expression suppressed Lapatinib toxicity. Thus in HCT116 cells Lapatinib adaptation can be mediated by altered expression of pro- and anti-apoptotic proteins that maintain mitochondrial function.
doi:10.1124/mol.108.047365
PMCID: PMC2574656  PMID: 18544666
Lapatinib; Ras; cell death

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