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:Detecting serum IL-37 concentrations and HBeAg seroconversion in chronic hepatitis B virus(HBV) patients during the treatment of telbivudine( LDT).Methods:Fifty patients with chronic hepatitis B were included in the study;and 20 healthy people were selected as the control group.The expression levels of interleukin ( IL)-37, IL-6 and CRP were measured by enzyme-linked immunosorbent assay.As the same time,the relationship between serum IL-37 concentrations and HBeAg seroconversion was dynamically observed at 0 w,12 w,24 w,36 w,48 w after treatment.Results:The serum levels of IL-37 in chronic HBV patients were higher than the control group at baseline(q=22.716,P<0.01).The serum levels of IL-37 were decreased in HBeAg seroconverted CHB patients(t=-19.480,P<0.001).The levels of IL-37 were positively correlated with ALT,IL-6 and CRP(r were 0.697,0.725, 0.895,respectively;all P<0.001).The levels of IL-37 and HBV DNA was no correlation(r=0.136,P>0.05).Conclusion:IL-37 may be involved in the process of HBV infection in CHB patients,and can reflect the degree of liver’ s inflammatory damage.IL-37 may play a significant role in the immune response of CHB patients with HBeAg seroconversion.In future,IL-37 may be an effective therapeutic measure to HBV infection.