Targeting of erbB3 receptor to overcome resistance in cancer treatment

Abstract

The erbB receptors, including the epidermal growth factor receptor (EGFR), erbB2 (also known as HER2/neu), erbB3 (or HER3), and erbB4 (or HER4), are often aberrantly activated in a wide variety of human cancers. They are excellent targets for selective anti-cancer therapies because of their transmembrane location and pro-oncogenic activity. While several therapeutic agents against erbB2 and/or EGFR have been used in the treatment of human cancers with efficacy, there has been relatively less emphasis on erbB3 as a molecular target. Elevated expression of erbB3 is frequently observed in various malignancies, where it promotes tumor progression via interactions with other receptor tyrosine kinases (RTKs) due to its lack of or weak intrinsic kinase activity. Studies on the underlying mechanisms implicate erbB3 as a major cause of treatment failure in cancer therapy, mainly through activation of the PI-3 K/Akt, MEK/MAPK, and Jak/Stat signaling pathways as well as Src kinase. It is believed that inhibition of erbB3 signaling may be required to overcome therapeutic resistance and effectively treat cancers. To date, no erbB3-targeted therapy has been approved for cancer treatment. Targeting of erbB3 receptor with a monoclonal antibody (Ab) is the only strategy currently under preclinical study and clinical evaluation. In this review, we focus on the role of erbB3-initiated signaling in the development of cancer drug resistance and discuss the latest advances in identifying therapeutic strategies inactivating erbB3 to overcome the resistance and enhance efficacy of cancer therapeutics.

Figure 1

ErbB3 interacts with erbB2 to activate signaling pathways leading to multi-drug resistance in breast cancer. Hetero-dimerization of erbB2 and erbB3 is able to induce activation of multiple downstream signaling pathways. In both luminal B and erbB2+ subtypes of human breast cancer, erbB2/erbB3 association may recruit IGF-1R to form a trimeric complex activating PI-3 K/Akt signaling and Src kinase and resulting in trastuzumab resistance. In erbB2+ breast cancer, interaction between erbB2 and erbB3 upregulates Survivin via a PI-3 K/Akt-dependent mechanism, and thereby confers paclitaxel resistance. In luminal B breast cancer, the erbB2/erbB3 hetero-dimers modulate ERα phosphorylation (activation) mainly through MEK/MAPK and/or PI-3 K/Akt signaling pathways, and subsequently alter tamoxifen sensitivity. These data support the hypothesis that targeting of erbB3 will significantly enhance the efficacy of those commonly used therapeutics in the treatment of erbB2+ breast cancer.

Figure 2

Current and novel therapeutic strategies targeting of erbB2 and/or erbB3 receptors for cancer therapy. Several erbB2-targeted therapies (trastuzumab, pertuzumab, T-DM1, and lapatinib) have being used in clinic, whereas no erbB3-targeted therapy has been approved for cancer treatment. Blocking Abs, such as MM-121, MM-111, AMG 888/U3-1287, and MP-RM-1/EV20, are the only agents being tested in early clinical and/or preclinical investigations. Our recent data show that entinostat, a class I HDAC inhibitor selectively downregulates erbB2/erbB3 via induction of specific miRNAs, miR-125a, miR-125b, and miR-205 in erbB2+ breast cancer cells. Further characterization demonstrates that these “sister” miRNAs (share common targets) act in concert to inhibit erbB2/erbB3 protein translation. Thus, the novel strategy, like cooperative miRNA targeting of erbB2/erbB3 may represent a new approach for cancer therapy.