Abstract 879: Investigating the activity of neratinib in human gastric cancer and gastric cancer cells, implications on clinical outcome and chemotherapy resistance

Abstract

Abstract Background. The EGF receptor (EGFR) kinase family plays important role in tumour growth and progression and has been a validated therapeutic target for lung cancers. Here, we examined the activity of an irreversible pan-HER tyrosine kinase inhibitor, neratinib, on kinase phosphorylation and cellular response in human gastric cancer. The study also examined the expression of the neratinib responsive kinases in relation to chemoresistance in human gastric cancer. Method. Tumour and normal gastric tissues from a cohort of 85 patients were obtained along with clinical outcome and therapeutic response to chemotherapy. The level of expression of a panel of protein kinases of interest, including EGFR family members, was quantitatively analysed using a protein based kinase array. Human gastric cancer cells (AGS and HGC27) were assessed for their sensitivity to neratinib, inhibitors of other candidate kinases and combinations thereof. Cellular growth, migration and matrix adhesiveness were evaluated using multiple in vitro platforms. Result. We identified a panel of kinases that were highly responsive to the treatment by neratinib in cell lines. In the gastric cancer cohort, expression of these kinases significantly correlated with the overall survival of the patients (p<0.001) and, together with node involvement, invasion, staging and type of surgery, was an independent prognostic indicator for the clinical outcome. Expression of the EGFR kinase family members EGFR, HER2, and HER4 was linked to poor clinical outcome. Expression of both neratinib response kinases and EGFR family members was also associated with therapeutic resistance to chemotherapies in the cohort of patients analyzed. In vitro, neratinib caused a concentration dependent inhibition of migration, matrix adhesiveness and growth in human gastric cancer cells. The migratory pace of the gastric cancer cells was particularly sensitive to neratinib. The role of two neratinib response kinases, Protein Kinase C iota (PKCi) and Mouse Double Minute 2 homologue (MDM2), was then further investigated. Interestingly, both PKCi and MDM2 were aberrantly expressed in gastric cancer tissues. In addition, the PKCi inhibitor Oncrasin-1 and the MDM2 antagonist Nutlin-3 both demonstrated synergy with neratinib in inhibiting adhesiveness and migration of the gastric cancer cells. Conclusion. Our data indicates that EGFR family members and other neratinib responsive kinases are aberrantly expressed in human gastric cancer and may be of prognostic value for the patients. In addition, gastric cancer cells are sensitive to neratinib, and displayed reduced migration when combined with inhibitors of PKCi or MDM2, two of the neratinib responsive kinases. Citation Format: W. G. Jiang, Tracey A. Martin, Sioned Owen, Lin Ye, Andrew J. Sanders, Yuxin Cui, Meng Xie, Shiqin Jia, Yongning Jia, Fiona Ruge, Francesca Avogadri-Connors, Alshad S. Lalani, Richard P. Bryce, Jiafu Ji. Investigating the activity of neratinib in human gastric cancer and gastric cancer cells, implications on clinical outcome and chemotherapy resistance [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 879.