Tumor cell growth and survival can often be impaired by inactivating a single 
oncogen- a phenomenon that has been called as "oncogene addiction." It is in 
such scenarios that molecular targeted therapies may succeed. among known 
oncogenes, the epidermal growth factor receptor (EGFR) has become the target of 
different cancer therapies. So far, however, the clinical benefit from 
EGFR-targeted therapies has been rather limited. a critical review of the large 
amount of clinical data obtained with anti-EGFR agents, carried out from the 
perspective of the oncogene addiction concept, may help to understand the causes 
of the unsatisfactory results. In this article we intend to do such an exercise 
taking as basis for the analysis a few case studies of anti-EGFR agents that are 
currently in the clinic. There, the "EGFR addiction" phenomenon becomes apparent 
in high-responder patients. We further discuss how the concept of oncogene 
addiction needs to be interpreted on the light of emerging experimental 
evidences and ideas; in particular, that EGFR addiction may reflect the 
interconnection of several cellular pathways. In this regard we set forth 
several hypotheses; namely, that requirement of higher glucose uptake by hypoxic 
tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted 
antibodies in EGFR-addicted tumors would induce stable disease by reversing the 
malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T 
cell response. Finally, we discuss possible reasons for the failure of certain 
combinatorial therapies involving anti-EGFR agents, arguing that some of these 
agents might produce either a negative or a positive trans-modulation effect on 
other oncogenes. It becomes evident that we need operational definitions of EGFR 
addiction in order to determine which patient populations may benefit from 
treatment with anti-EGFR drugs, and to improve the design of these therapies.