The ErbB2 receptor in gastric cancer: the quick-change artist

The ErbB family of receptors is providing the oncogenic signals necessary to cells to become transformed. In gastric cancer (GC) the ErbB2 (HER2) expression is associated with a poor prognosis, but addition of ErbB-targeted therapeutics to chemotherapy has produced unsatisfactory results with moderate improved outcomes for patients. The ToGA trail has revolutionized the treatment of GC, introducing the use of trastuzumab and changing the poor prognosis of these patients. However, this study reported only a modest prolongation of progression-free survival (PFS) and overall survival (OS) in patients with high expression of ErbB2 protein, with a large percentage of initially good responders, then becoming refractory to therapy within one year. These findings indicate the occurrence of resistant phenotypes arising from diverse adaptive and genetic changes. Due to the promiscuity of ErbB2 in the EGFR family signaling network, the use of ErbB targeted mono-therapies certainly contributes to a redistribution of the stoichiometry among receptors leading to the activation of compensatory pathways, suggesting that survival of cancer cells is sustained, at least in part, by the network of the ErbB receptors and their ligands. For these reasons, the use of combination therapies is becoming the most logical strategy for any type of cancer treatment, including GC. In this review we summarize information regarding mechanisms, pathways and molecules involved in the resistance to ErbB-targeted molecules with the intent to provide rational guidelines for developing more efficient therapeutic approaches.