ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer

• DOI: 10.1073/pnas.1901765116
• Publication Date: 2019-08-09T23:45:13Z
• Authors: Shigeru Hashimoto; Shotaro Furukawa; Ari Hashimoto; Akio Tsutaho; Akira Fukao; Yurika Sakamura; Gyanu Parajuli; Yasuhito Onodera; Yutaro Otsuka; Haruka Handa; Tsukasa Oikawa; Soichiro Hata; Yoshihiro Nishikawa; Yusuke Mizukami; Yuzo Kodama; Masaaki Murakami; Toshinobu Fujiwara; Satoshi Hirano; Hisataka Sabe
• Keywords: PD-L1; Models, Molecular; 0301 basic medicine; mRNA translation; 490; B7-H1 Antigen; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; Cell Line, Tumor; Biomarkers, Tumor; Humans; Receptors, Platelet-Derived Growth Factor; ARF6; RNA, Messenger; Immune Evasion; Binding Sites; ADP-Ribosylation Factors; mevalonate pathway; Prognosis; Immunohistochemistry; 3. Good health; Gene Expression Regulation, Neoplastic; Pancreatic Neoplasms; PNAS Plus; ADP-Ribosylation Factor 6; pancreatic driver oncogenes; Mutation; Tumor Suppressor Protein p53; Protein Binding; Signal Transduction

Significance Pancreatic ductal carcinomas (PDACs) have been extensively studied regarding their genomic alterations, microenvironmental intercommunication, and metabolic reprogramming. However, identification of the protein machinery of tumor cells that eventually drives malignancy as a result of driver mutations, and their associated events, is highly anticipated toward the development of precision medicine. The lack of such information regarding PDACs has hindered the elucidation of mechanisms driving malignancies, leaving them incurable. Here we demonstrated that the 2 well-known pancreatic driver mutations cooperatively activate a specific signaling pathway that promotes tumor invasion and immune evasion properties. Our results provide insights into the molecular basis by which malignancies often develop in parallel with oncogenesis and PDAC cell growth, as well as druggable targets for immunotherapies.