Abstract 89: Reduced kinase D-interacting substrate of 220kDa (Kidins220) in pancreatic cancer promotes EGFR/ERK signaling and disease progression

Abstract

Abstract Kidins220 (Kinase D-Interacting Substrate, 220kDa), also known as ARMS (ankyrin repeat-rich membrane spanning) is a transmembrane scaffolding protein. Kidins220 acts as a platform for protein-protein interactions to coordinate cell plasticity, migration and neural growth receptor signalling. Present study aims to investigate the involvement of Kidins220 in the disease progression of pancreatic cancer. Pancreatic tumors (n=149) together with paired adjacent background tissues were collected at Peking University Cancer Hospital with written consent from the patients and also an ethical approval from the Peking University Cancer Hospital Research Ethics Committee. Kidins220 transcript levels were determined using real-time PCR. Relevance of Kidins220 transcript levels and pathologic/clinical features was analyzed. Knockdown of Kidins220 was carried out with a lentiviral Kidins220 shRNA. Immunohistochemical (IHC) staining of Kidins220 was performed on a pancreatic tissue microarray (TMA) (PA2081a, US Biomax, Inc., Rockville, MD, USA). A decreased expression of Kidins220 transcripts was observed in pancreatic cancer tissues in comparison with the paired background control (P=0.029). According to the TNM staging, early stage tumors (TNM 1&2) expressed higher levels of Kidins220 transcripts compared with its expression in more advanced tumors (TNM 3&4 stage, p=0.0034). In line with the finding from the Beijing pancreatic cancer cohort, a reduced expression of Kidins220 protein was seen in the pancreatic carcinomas of the TMA using IHC, p<0.001 compared with normal control. Moreover, based on the IHC results, primary tumors with distance metastases exhibited a decreased level of Kidins220 expression compared to those without metastasis. Knockdown of Kidins220 in pancreatic cancer cell lines PANC1 and MIA-PaCa-2 promoted migration and invasion of both cell lines. A protein array analysis (KinexTM) revealed an increased EGFR phosphorylation in the Kidins220 knockdown pancreatic cancer cell lines which was confirmed with Western blot. The Kidins220 knockdown-resulted increased invasion was eliminated by targeting EGFR using both gefitinib or with the irreversible pan-HER tyrosine kinase inhibitor, neratinib. Proliferation assays showed that neratinib was more effective to inhibit proliferation of PANC-1 and Mia-PaCa-2 cells at a range of concentration from 20nM to 2μM. In conclusion, the expression of Kidins220 was reduced in pancreatic cancer and the reduced expression in primary tumors was associated with distant metastases. Reduced Kidins220 expression promoted migration and invasion of pancreatic cancer cells through an upregulation of EGFR. The therapeutic potential of neratinib or gefitinib for reduced kidins220 relevant disease progression and metastasis in pancreatic cancers is yet to fully investigated. Citation Format: Shuo Cai, Ping-Hui Sun, Xiangyu Gao, Ke Ji, Xiuyun Tian, Chunyi Hao, Bilal Al-Sarireh, Paul Griffiths, Steven Hiscox, Jared Tonkington, Jun Cai, Wen G. Jiang, Lin Ye. Reduced kinase D-interacting substrate of 220kDa (Kidins220) in pancreatic cancer promotes EGFR/ERK signaling and disease progression [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 89.