Background/Aims: Biliary tract cancer (BTC) frequently harbors KRAS mutations, which are associated with resistance to traditional treatment and a poor prognosis. Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL. Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against KRAS-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using KRAS-mutant and KRAS-wild type BTC cell lines, patient-derived xenografts (PDX), and KRAS oncogene-driven tumor models, as well as other KRAS-mutant cancer cell lines. Results: Initially, we discovered that the loss of GATA2 reduced the viability of KRAS-mutant but not KRAS-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in KRAS-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in KRAS-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced KRAS-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a KRAS oncogene-driven tumor model, as well as in other KRAS-mutant cancer cell lines. Conclusions In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in KRAS-mutant BTC and potentially other cancers.

Objective To analyze the molecular characteristics of human pathogenic avian influenza A H7N9 virus.Methods The gene sequences of avian influenza A H7N9 virus (30 human-originated and 15 avian-originated) isolated in Zhejiang province from 2013 to 2015 were downloaded from Global Initiative on Sharing Avian Influenza Data ( GISAID), and then the evolution characteristics, the sites related to receptor binding, virulence and drug resistance of H7N9 virus were analyzed by MEGA 6.0 software. Results There were minor differences in HA and NA genes between human H7N9 virus strains and poultry reference strains in Zhejiang province with the homology of 98.0%-100.0% and 97.4%-100.0%, respectively.Viral amino acid variation showed that 30 representative strains had mutations at 226 (Q226L/I) and 186(G186V) sites in HA protein, and all strains isolated from 2015 had A134V mutation;one strain had R294K mutation in NA gene;19 strains had E627K mutation in PB2 and 2 strains had D701N mutation;mutation S31N was found in M2 gene in all isolates; and all HA cleavage sites were PEIPKGR↓GLF, indicating low pathogenic strain.Conclusions The homology of HA and NA genes is high between poultry reference strains and human H7N9 virus strains in Zhejiang province during 2013 and 2015.Strains have some significant mutations of amino acid in HA and NA protein.All isolates show ion channel inhibitors ( Amantadine) resistance, and some isolates show resistance mutations with neuraminidase inhibitors.