Abstract 4577: Fibroblast growth factor receptor-4 (FGFR-4) as a novel therapeutic target for pancreatic cancer

Abstract

Abstract The fibroblast growth factor receptor (FGFR) family plays crucial roles in development, tissue repair, and malignant tumors. FGFR-1, -2, and -3 each exist in two isoforms, IIIb and IIIc, due to alternative splicing of the extracellular domain, whereas FGFR-4 does not have these isoforms. FGFR-4 is reportedly over-expressed in various cancers such as breast, prostate, hepatocellular, ovarian, gastric, colorectal, and pancreatic cancers, wherein it contributes to tumor progression. Recent studies have shown that a decrease in FGFR-4 levels suppresses the aggressiveness of gastric, colorectal, and ovarian cancers. We found that pancreatic cancer cell lines expressed similar levels of the IIIb and IIIc isoforms of FGFR-1 to -3, but showed different FGFR-4 levels. These findings suggest that the cancer cells surviving after treatment with recently developed anti-FGFR drugs, which target FGFR-1 to -3, tend to express high levels of FGFR-4. Moreover, a single-nucleotide polymorphism (SNP) in exon 9 of the gene encoding FGFR-4 that results in the substitution of glycine with arginine at codon 388 (388 Gly/Arg) in the transmembrane domain is associated with poor outcomes of high-grade soft tissue sarcoma, prostate, lung, head and neck carcinoma, and advanced and treatment-resistant breast cancer. It has been reported that 40-50% of Caucasians carry at least one copy of the 388 Gly/Arg SNP of FGFR-4. In the present study, we examined the expression and roles of the 388 Gly/Arg SNP in pancreatic cancer and tried to clarify whether FGFR-4 may be a novel therapeutic target for cancer treatment. In human pancreatic tissues, FGFR-4 was weakly localized in the normal exocrine and endocrine pancreas, and was strongly expressed in 67 of 136 pancreatic ductal adenocarcinoma cases (49%). FGFR-4 expression positively correlated with larger primary tumors and more advanced stages of pancreatic cancer. FGFR-4 mRNA was expressed in 5 pancreatic cancer cell lines at various levels, and the mutation in codon 388 was detected in 3 of the cell lines, including PK-1 cells. A short hairpin RNA expression vector targeting FGFR-4 was stably transfected to these mutant-expressing PK-1 cells (388 Gly/Arg), which then showed lower growth rates and cell migration and invasion abilities compared to sham vector-transfected cells. DNA microarray analysis showed that decreased expression of FGFR-4 in PK-1 cells altered the expression levels of molecules related to cellular movement, cellular development, and cell-to-cell signaling and interactions. FGF-19—one of the major ligands for FGFR-4—was expressed in all 5 of the pancreatic cancer cell lines tested. These findings suggest that inhibition of the expression of FGFR-4 harboring the 388 Gly/Arg SNP may be a novel therapeutic strategy for pancreatic cancer, especially after treatment with the newly developed anti-FGFR-1 to -3-targeted drugs. Citation Format: Toshiyuki Ishiwata, Hisashi Yoshimura, Yoko Matsuda, Shunji Ishiwata. Fibroblast growth factor receptor-4 (FGFR-4) as a novel therapeutic target for pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4577.