ErbB family members are functionally redundant. The critical functions of ErbB signaling include dimerization, tyrosine phosphorylation, and activation of some redundant downstream signaling molecules. Even though trastuzumab inhibits ErbB-2 phosphorylation, it rarely blocks the dimerization of ErbB-2 with other ErbB family members. Recently, long-term trastuzumab treatment of ErbB-2-positive breast cancer cells showed increase in EGFR and ErbB-3 expression. This indicates that alternate ErbB family dimers, such as ErbB-1/ErbB-1 and ErbB-1/ErbB-3 dimers, could possibly circumvent trastuzumab-induced blockade and promote growth and survival of breast tumors. Moreover, TGF-β has been shown to activate ErbB-3 in ErbB-2-overexpressing cells and subsequently the PI3’K pathway by enhancing phosphorylation and translocation of ADAM17 to the cell surface. This results in an increase in ErbB ligand shedding and desensitization of these cells to trastuzumab. Interestingly, from EGFR and ErbB-3 receptor knockdown studies, ErbB-3 has been shown to play a crucial role over EGFR in ErbB-2-amplified breast cancer. Therefore, a promising approach to treat trastuzumab resistance would be to design monoclonal antibodies that can be directed at dimerization of all the ErbB family members. Pertuzumab is a humanized, monoclonal antibody that was designed to specifically target hetero-dimers of the ErbB family. Recently, pertuzumab has shown significant efficacy when combined with trastuzumab in ErbB-2-positive metastatic breast cancer.

Loss or decreased expression of negative regulators of signaling pathway activated by ErbB receptors has been implicated in resistance to trastuzumab. For example, the tumor suppressor phosphatase and tensin homolog (PTEN) is a negative regulator of the PI3’K/AKT signaling pathway. PTEN acts as a phosphatase to dephosphorylate PIP3 back to PIP2. This dephosphorylation results in inhibition of AKT pathway and subsequently controls cell survival, proliferation, and growth. ErbB-2-overexpressing breast tumors that express little to undetectable levels of PTEN respond poorly to trastuzumab therapy. Concurrently, constitutive PI3’K/AKT kinase activity has also been shown to promote growth and proliferation of breast tumors. ErbB-2-overexpressing breast cancer cells that have heightened PI3’K/AKT signaling and reduced PTEN expression were shown to be the most sensitive to PI3’K or mTOR inhibitors. These inhibitors when combined with trastuzumab were able to overcome resistance both in vitro and in vivo breast tumor models. These results suggest that loss or low expression of PTEN and subsequent high AKT kinase activity induce trastuzumab resistance and serve as predictors of poor response to trastuzumab. Thus, inhibitors of the PI3’K/AKT/mTOR signaling pathway need to be explored in combination with trastuzumab to prevent trastuzumab resistance. However, when tumor samples from trastuzumab-treated women were analyzed for PTEN and AKT status, the expression levels of PTEN and AKT did not significantly correlate with response to trastuzumab-based therapy, time to disease progression, or incidence of CNS metastases.