Abstract
ErbB family members represent important biomarkers and drug targets for modern precision therapy. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. This review summarizes the current understanding of ErbB proteins in cell signalling and cancer and describes the molecular rationale of prominent cases of ErbB oncoprotein addiction in different cancer types. In addition, we have highlighted experimental technologies for the development of innovative cancer cell models that accurately predicted clinical ErbB drug efficacies. In the future, such cancer models might facilitate the identification and validation of physiologically relevant novel forms of oncoprotein and non-oncoprotein addiction or synthetic lethality. The identification of genotype-drug response relationships will further advance personalized oncology and improve drug efficacy in the clinic. Finally, we review the most important drugs targeting ErbB family members that are under investigation in clinical trials or that made their way already into clinical routine. Taken together, the functional characterization of ErbB oncoproteins have significantly increased our knowledge on predictive biomarkers, oncoprotein addiction and patient stratification and treatment.
Highlights
The ErbB receptor tyrosine kinase family consists of four cell surface receptors, ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4 [1]
Two ligands selectively bind to ErbB3, Neuregulin (Nrg 1 and 2) and seven ligands interact with ErbB4 (BTC, HB-epidermal growth factor (EGF), EPR, Nrg1-4)
A decade has elapsed since the concept of oncogene addiction has first emerged [52]
Summary
The ErbB receptor tyrosine kinase family consists of four cell surface receptors, ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4 [1]. ErbB3 contains no functional kinase domain, but rather displays several tyrosine phosphorylation sites that provide binding sites for signalling proteins that mediate activation of downstream effector molecules such as the Akt/PKB pathway [8]. The ErbB effectors include the PI3K-Akt-mTOR pathway, the RAS-RAF-MEK-ERK pathway and the phospholipase C gamma (PLCγ) pathway [1] These signalling cascades regulate a vast variety of physiological events including cell proliferation, apoptosis, angiogenesis, cell adhesion and motility, embryonic development, and organogenesis [10,11,12]. The pathway contributes to cell survival, cell growth and proliferation [22,23,24] In this regard, the small GTPase RAS acts as a central signalling node that can activate many different downstream effector proteins [25,26,27]. A new generation of drugs that selectively target the ErbB oncoproteins has demonstrated impressive therapeutic efficacy in the clinic [1,3,51]
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