Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) have an important role in the initiation and progression of various types of cancer. Inhibitors targeting these receptor tyrosine kinases are some of the most successful targeted anticancer drugs widely used for cancer treatment; however, cancer cells have mechanisms of intrinsic and acquired drug resistance that pose as major obstacles in drug efficacy. Extensive studies from both clinical and laboratory research have identified several molecular mechanisms underlying resistance. Among them is the role of signaling cross-talk between the EGFR/HER2 and other signaling pathways. In this review, we focus particularly on this signaling cross-talk at the receptor, mediator and effector levels, and further discuss alternative approaches to overcome resistance. In addition to well-recognized signaling cross-talk involved in the resistance, we also introduce the cross-talk between EGFR/HER2-mediated pathways and pathways triggered by other types of receptors, including those of the Notch, Wnt and TNFR/IKK/NF-κB pathways, and discuss the potential role of targeting this cross-talk to sensitize cells to EGFR/HER2 inhibitors.
