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Fibrolamellar hepatocellular carcinoma (FLC) is a lethal pediatric cancer affecting adolescents and young adults. Besides surgical resection, there is no approved and effective therapy. FLC is driven by a fusion oncokinase, DNAJB1-PRKACA, that arises from a deletion fusing exon 1 of DNAJB1 and exons 2-10 of PRKACA, the catalytic subunit of protein kinase A. Expression of this chimeric oncokinase is capable of recapitulating the key histologic and transcriptomic features of FLC. Using PDXs, we tested therapeutics that have been used clinically for FLC or that target pathways identified via the transcriptomic signature of FLC, in addition to an agnostic library of clinical-stage drugs. Several compounds were identified with a varying degree of efficacy in different PDX lines as compared to our control line, primary human hepatocytes. One of the top hits was irinotecan, and its active metabolite SN38. Irinotecan is a topoisomerase I inhibitor and is clinically utilized in a wide variety of adult and pediatric cancers. A second top hit was Navitoclax, an inhibitor of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Tool compounds that targeted Bcl-xL, but not bcl-2 were efficacious. This suggested a possible link between Bcl-xL, which is overexpressed in some PDX lines, and the resistance profile they showed in our screen. Unfortunately, Navitoclax has an on-target and dose-limiting toxicity of thrombocytopenia, which limits its clinical application. DT2216 is a VHL-based PROTAC that degrades Bcl-xL. DT2216 has two potential benefits over Navitoclax: 1) DT2216 is a more potent than Navitoclax against various Bcl-xL dependent tumor cells; and 2) it is less toxic to platelets than Navitoclax by targeting Bcl-xl to VHL that is poorly expressed in platelets to avoid induction of severe thrombocytopenia. A phase 1 clinical trial of DT2216 in relapsed/refractory malignancies is now ongoing (NCT04886622). We tested if the combination of DT2216 and irinotecan might have a therapeutic potential in FLC. Indeed, in vitro screening of the proposed combo, DT2216 and SN38, showed an additive or a synergistical effect in 4 validated FLC cell lines. We tested both the efficacy of DT2216 on Bcl-xL levels in FLC as well as platelet counts to identify any developing thrombocytopenia. DT2216 was less disruptive to platelets than Navitoclax at therapeutically relevant pre-clinical doses. Next, we tested 4 of our PDX models for FLC using various dosing regimens to identify the most efficacious regimen with the minimum side effects. Mice cohorts were evaluated for weight loss and tumor volume. Mice treated with DT2216 and SN38 showed consistent therapeutic benefit which was not evident in controls and less notable as monotherapy. In conclusion, TOPO1 and Bcl-xL prove to be promising targets of interest in FLC. Targeting both with DT2216 and irinotecan leads to tumor shrinkage in pre-clinical models and offer a potential therapeutic/pharmacological intervention for FLC. Citation Format: Bassem Shebl, Gadi Lalazar, Denise Ng, Tova Finkelstein, Guangrong Zheng, Peiyi Zhang, Carly Rosemore, Michael Ortiz, Daohong Zhou, Sanford Simon, Philip Coffino. Targeting Bcl-xL in fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3888.