Interleukin-1β as target to induce synthetic lethality in KRAS mutant biliary tract cancer

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 <i>KRAS</i>-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using <i>KRAS</i>-mutant and <i>KRAS</i>-wild type BTC cell lines, patient-derived xenografts (PDX), and <i>KRAS</i> oncogene-driven tumor models, as well as other <i>KRAS</i>-mutant cancer cell lines.Results: Initially, we discovered that the loss of GATA2 reduced the viability of <i>KRAS</i>-mutant but not <i>KRAS</i>-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in <i>KRAS</i>-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in <i>KRAS</i>-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced <i>KRAS</i>-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a <i>KRAS</i> oncogene-driven tumor model, as well as in other <i>KRAS</i>-mutant cancer cell lines.Conclusions: In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in <i>KRAS</i>-mutant BTC and potentially other cancers.