Abstract 5244: Neratinib induced HER2 dependent and independent intracellular signaling events in human breast cancer cells and the clinical implications

Abstract

Abstract Background. Neratinib is an orally available irreversible pan-HER receptor tyrosine kinase inhibitor that has clinical benefit in patients with HER2-positive and HER2-mutated breast cancer. Neratinib also targets the other two members of the HER family, namely EGFR and HER4. However, tentative evidence suggests that neratinib may affect kinases of non-HER family. In the present study, we aimed to explore the pattern of kinases targeted by neratinib, in the context of HER2 non-amplified cancer cells and explored the potential clinical implications. Method. A panel of HER2-low/medium-expressing (MCF-7 and ZR-75-1) and HER2- negative (MDA-MB-231 and BT549) human breast cancer cells were used. The response of a panel of 304 kinases to neratinib was screened using the kinase antibody array. Cellular toxicity was quantified using a colorimetric method. Candidate neratinib-responsive kinases were subject to analyses against the survival of a breast cancer cohort as well as a public database for additional validation. The protein expression level of the kinase targets identified was also validated on tissue arrays from breast cancer by immunohistochemistry. Result. Of all the kinases tested, thirty-six were found to be influenced by neratinib, either via activation or suppression of their phosphorylation. Based on the differential responses to neratinib in HER2 negative and positive breast cancer cells, a small panel of the kinases were classified as HER2 independent. Using clinical cohorts, these kinases collectively had predictive value for the overall survival of the patients (p<0.0001). We further analysed one of the candidate kinases, namely salt inducible kinase-1 (SIK1) and the SIK family in relation with HER2. HER2 expression was found significantly correlated with both SIK1 (r=0.46, p<0.001) and also other two SIK family members. SIK1 protein staining in the tissue array was found to be aberrant in breast tumours. Conclusion. Neratinib has an effect on a subset of HER2 independent kinases in breast cancer cells. These kinases had a prognostic value on patient's survival and correlated with HER2 expression, as in the case of the SIK family.This finding may have important implication in understanding the biology of HER2 inhibitors such as neratinib. Citation Format: W. G. Jiang, Tracey A. Martin, Sioned Owen, Ling Xin, Yinhua Liu, Fiona Ruge, Francesca Avogadri-Connors, Alshad S. Lalani, Richard P. Bryce, Eleri Davies. Neratinib induced HER2 dependent and independent intracellular signaling events in human breast cancer cells and the clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5244.