RT Journal Article
SR Electronic
T1 Lapatinib Resistance in HCT116 Cells Is Mediated by Elevated MCL-1 Expression and Decreased BAK Activation and Not by ERBB Receptor Kinase Mutation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 807
OP 822
DO 10.1124/mol.108.047365
VO 74
IS 3
A1 Aditi Pandya Martin
A1 Anna Miller
A1 Luni Emad
A1 Mohammed Rahmani
A1 Teneille Walker
A1 Clint Mitchell
A1 Michael P. Hagan
A1 Margaret A. Park
A1 Adly Yacoub
A1 Paul B. Fisher
A1 Steven Grant
A1 Paul Dent
YR 2008
UL http://molpharm.aspetjournals.org/content/74/3/807.abstract
AB We have defined some of the mechanisms by which the kinase inhibitor lapatinib kills HCT116 cells. Lapatinib inhibited radiation-induced activation of ERBB1/2, extracellular signal-regulated kinases 1/2, 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 epidermal growth factor (EGF)-stimulated ERBB1 phosphorylation in adapted cells. Coexpression of dominant-negative ERBB1 and dominant-negative ERBB2 inhibited basal and EGF-stimulated ERBB1 and ERBB2 phosphorylation in parental and adapted 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. Overexpression of BCL-XL protected parental cells from lapatinib toxicity. Knockdown of MCL-1 expression enhanced lapatinib toxicity in adapted cells that was reverted by knockdown of BAK expression. Inhibition of caspase function modestly reduced lapatinib toxicity in parental cells, whereas knockdown of apoptosis-inducing factor expression suppressed lapatinib toxicity. Thus, in HCT116 cells, lapatinib adaptation can be mediated by altered expression of pro- and antiapoptotic proteins that maintain mitochondrial function.