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.
Highlights
ErbB3 (HER3) belongs to the erbB (HER) receptor family of type I receptor tyrosine kinases (RTKs)
Conclusions and future directions Research on erbB receptors has long been focused on dysregulation of tyrosine kinase activity of epidermal growth factor receptor (EGFR) and erbB2 in human cancers
ErbB3 may be considered as a valuable biomarker to predict the efficacy of EGFR- and/ or erbB2-targeted therapy in the treatment of nonsmall cell lung cancer (NSCLC) and erbB2+ breast cancer, respectively
Summary
ErbB3 (HER3) belongs to the erbB (HER) receptor family of type I receptor tyrosine kinases (RTKs). Our early studies showed that co-expression of erbB2 and erbB3 in human breast cancer cell lines induced activation of PI-3 K/Akt signaling and was associated with an increased resistance to multiple chemotherapeutic agents, such as paclitaxel, doxorubicin, 5-fluorouracil, etoposide, and camptothecin [60]. A new anti-erbB3 Ab (MP-RM-1) and its humanized version (named EV20) both have been shown to exhibit antitumor activity against various cancer types in vitro and in vivo [93,94] Because this Ab has the ability to inhibit both ligand-dependent and -independent activation of erbB3 [93,94], we speculate that EV20 may have a much broader effect on blocking erbB3 signaling than those Abs (like MM-121) which only prevent ligand-induced activation of erbB3, and exert more potent activity to overcome drug resistance in cancer therapy. Detailed analysis is warranted to test this innovative idea in vitro and in vivo
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