Abstract: The HER (ErbB) receptor tyrosine kinase receptors are implicated in many cancers and several anti-HER treatments are now approved. In recent years, a new group of compounds that bind irreversibly to the adenosine triphosphate binding pocket of HER receptors have been developed. One of these compounds, neratinib, has passed preclinical phases and is currently undergoing various clinical trials. This manuscript reviews the preclinical as well as clinical data on neratinib. As a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clinical trials in breast cancers and other solid tumors, including those with HER2 mutation. Earlier studies have already shown promising clinical activity for neratinib. However, more translational research is required to investigate biomarkers that could help to predict response and resistance for selection of appropriate patients for treatment with neratinib, either as monotherapy or in combination with other drug(s).

Keywords: neratinib, HKI 272, pan-HER inhibitor, irreversible tyrosine kinase inhibitor, HER (ErbB), breast cancer

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The family of HER (ErbB) receptor tyrosine kinases consists of four members, ie, epidermal growth factor receptors [EGFR (HER1 or ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4)].Overexpression, mutation, or aberrant activity of these receptors has been implicated in various types of cancer. HER2 is overexpressed in approximately 15%–20% of all breast cancers1 and is correlated with poor prognosis.2 HER receptors comprise an extracellular domain, a single transmembrane domain, and an intracellular tyrosine kinase domain.3 A disintegrin and metalloproteinases (ADAMs) shed the ligands that are needed for HER member activation. Eleven ligands are known to bind to the different receptors of the family, as shown in Figure 1;3 however, HER2 does not have a known ligand.4 Ligand binding induces a conformational change in HER receptors 1, 3, and 4, which exposes the dimerization domain. This facilitates homodimerization or heterodimerization and transphosphorylation of the tyrosine kinase domains.5 Subsequently, downstream signaling pathways, most prominently the phosphatidylinositide 3-kinase and mitogen-activated protein kinase pathways, are activated and promote survival and proliferation.6–8 HER2 adopts a constant “open” conformation, with the dimerization domain being always available.9 It was shown to be the preferred dimerization partner within the HER receptor network and it can also form potent homodimers.10