Abstract 1217A: Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells

Abstract

Abstract Background: Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. No driver gene responsible for the malignant potential of SGC has not been identified. Next-generation sequencing (NGS) technology has defined as the genomic landscape of various types of cancers, and has elucidated a number of novel driver mutations of gastric cancer. RHOA and CDH1 are characteristic mutations for SGC, but these mutations are not druggable. Novel molecular target therapy has been necessary for SGC based on its biological behavior. Objective: We sought to identify the characteristic driver gene which is responsible for SGC. Methods: DNA was isolated from six human SGC cell lines: OUCM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12, and OCUM-14. The mutational status of 90 cancer-associated genes was examined by next-generation sequencing. The expression level of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) in 708 gastric cancers was examined immunochemically, and the correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were analyzed. Results: The nonsynonymous mutations of STK11/LKB1 gene were found in three of the six SGC cell lines. Nonsense mutation of STK11/LKB1, which was associated with STK11/LKB1 loss (Y253*), was found in OCUM-12 cells, and missense mutation of STK11/LKB1 (F354L) was found in OCUM-2M cells and OCUM-14 cells. Rapamycin, an inhibitor of STK11/ AMP-activated protein kinase (AMPK)/mammalian target of rapamycin signaling (mTOR), showed inhibitory effects of SGC cells harboring STK11/LKB1 mutation. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth, and nodal involvement, in compared to the high STK11/LKB1 expression group. The 5-year survival rate of patients with low STK11/LKB1 expression was significantly poorer compared to those with high STK11/LKB1 expression (p<0.001). A conditional multivariate analysis showed that STK11/LKB1 expression status was an independent prognostic factor. Conclusion: SGC cells frequently showed the nonsynonymous mutations of STK11/LKB1. STK11/LKB1 mutation might be responsible for the malignant potential of SGC. STK11/AMPK/mTOR signaling might be one of the therapeutic targets for patients with SGC.1 Citation Format: Sadaaki Nishimura, Masakazu Yashiro, Tomohiro Sera, Yurie Yamamoto, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Kenji Kuroda, Tomohisa Okuno, Masaichi Ohira. Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1217A.