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.