The clinical efficacy of tyrosine kinase inhibitors supports the dependence of 
distinct subsets of cancers on specific driver mutations for survival, a 
phenomenon called "oncogene addiction." We demonstrate that PUMA and BIM are the 
key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with 
amplification of the gene encoding human epidermal growth factor receptor 2 
(HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. 
The BH3 domain containing proteins BIM and PUMA can directly activate the 
proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to 
caspase activation and apoptosis. We delineated the signal transduction pathways 
leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. 
Inhibition of the mitogen-activated or extracellular signal-regulated protein 
kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway caused 
increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase 
(PI3K)-AKT pathway triggered nuclear translocation of the FOXO transcription 
factors, which directly activated the PUMA promoter. In a mouse breast tumor 
model, the abundance of PUMA and BIM was increased after inactivation of HER2. 
Moreover, deficiency of Bim or Puma impaired caspase activation and reduced 
tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma 
impeded the regression of EGFR(L858R)-driven mouse lung tumors upon inactivation 
of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the 
sentinels that interconnect kinase signaling networks and the 
mitochondrion-dependent apoptotic program, which offers therapeutic insights for 
designing novel cell death mechanism-based anticancer strategies.