Profile of neratinib and its potential in the treatment of breast cancer

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).

Adaptive Randomization of Neratinib in Early Breast Cancer

“…5,6 There is also evidence of preclinical activity against HER2-negative tumor cells 7,8 , suggesting the possibility that pan-ErbB/HER kinase activity against EGFR and possibly HER4 might have activity beyond HER2+ tumors. 9 The adaptive randomization approach used in I-SPY2 offers the ability to test this possibility while minimizing exposure of patients with HER2-tumors to treatments that are ineffective. Because neratinib was introduced prior to dual targeting of HER2 becoming standard of care in neoadjuvant treatment, it was tested against, rather than being combined with, trastuzumab.…”

Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor, Neratinib, in Cancer Cells

“…Neratinib (Nerlynx), a second‐generation TKI with dual specificity against EGFR and HER2, was found to be effective despite the T790M resistance mutation in EGFR and binds irreversibly to EGFR and HER2 7, 8. Neratinib was approved last year by the U.S. Food and Drug Administration for treatment of early‐stage HER2‐positive breast cancer 9.…”

“…Neratinib targets EGFR and HER28 and it is important to monitor the distribution not only of neratinib in cells but also of these receptors as well as of lysosomes. Neratinib is a weak base that can be protonated in an acidic environment, and lysosomes are most likely sites for neratinib accumulation 26.…”

“…Neratinib possesses an α,β‐unsaturated carbonyl moiety (acrylamide group) which forms a covalent bond with Cys797 of EGFR and with Cys805 of HER27, 8 through a Michael addition reaction. Neratinib also retains electrophilic reactivity to the Cys residue of glutathione (GSH) by forming a GSH adduct 28.…”

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

“…In addition, the reaction to neratinib was associated with HER2 and phosphorylated HER2 levels, but not with EGFR levels, in vitro [88]. Neratinib binds to cysteine residues Cys-773 and Cys-805 in EGFR and HER2, respectively [89]. Because of this particular authoritative work, higher specificity of the compound is accomplished.…”