Potential Value of AURKA and CDK6 Amplification for the Response of Patients With Gastric Cancer to Neoadjuvant Chemotherapy.

Abstract

Many patients respond poorly to neoadjuvant chemotherapy (NACT), negatively affecting the surgical success rate. Identifying effective biomarkers and understanding the potential resistance mechanisms are urgently needed. Data of 18 patients with advanced stomach cancer who were treated with NACT categorized according to tumor regression grade into major histological response (MJHR) and nonhistological response (NHR) groups were retrospectively analyzed. Genomic signatures associated with the response to NACT were identified using whole-exome and RNA sequencing. Extraction of molecular signatures revealed increased deficient mismatch repair signature and tumor mutation levels in the NHR group. Compared to the MJHR group, the NHR group was also characterized by a greater number of copy number alterations (p = 0.08), which was further confirmed by RNA sequencing, and upregulation of aurora kinase A (AURKA) (p = 0.05) and cyclin-dependent kinase 6 (CDK6) (p = 0.049). Western blot analysis and immunohistochemical analyses further confirmed high CDK6 (p < 0.01/p < 0.0001) and AURKA (p < 0.01/p < 0.001) expression levels in the NHR group. Finally, palbociclib, an inhibitor of CDK4/6, effectively inhibited the proliferation (p < 0.05) and induced apoptosis of oxaliplatin-resistant gastric cancer cells (p < 0.01) in vitro. These findings support the potential value of AURKA and CDK6 amplification, as well as their effects on the tumor microenvironment, in predicting poor outcomes of NACT in patients with locally advanced gastric cancer. Thus, CDK4/6 inhibitors could be used to treat NACT-resistant patients with gastric cancer.