Retinoic acid treatment suppresses fibrolamellar carcinoma growth
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ABSTRACT: Fibrolamellar carcinoma (FLC) is a devastating, early-onset rare cancer for which there is no effective standard of care. FLC tumors are initiated and likely also maintained by the fusion oncoprotein DNAJ-PKAc (DP). Strategies to therapeutically target DP are underway but remain challenging. Alternate therapeutic approaches are needed in order to maximize the potential benefit for patients. In this study, to identify candidate compounds for drug repurposing, we re-analyzed publicly available RNA-seq data in FLC and non-malignant liver (NML) tissue. We noted that retinoid metabolism, a normal function of a healthy liver, is strikingly suppressed in FLC, which led to the hypothesis that FLC tumors may be responsive to all-trans retinoic acid (ATRA). To test this hypothesis, we treated FLC tumor cells in culture, established from a patient-derived xenograft (PDX) mouse model, with ATRA and found by RNA-seq that well-established molecular markers of PKA signaling and FLC tumors are significantly reduced. Moreover, ATRA treatment markedly diminished cell viability, proliferation, and colony forming capability. We also demonstrated that ATRA sensitizes FLC cells to apoptotic induction by the TLR3 ligand, poly(I:C). Next, using patient tissue slices, we confirmed that ATRA reduces cell viability only in tumors and not in adjacent NML tissue. Finally, we performed in vivo studies in PDX mice to show that ATRA significantly suppresses FLC tumor growth. These findings motivate a more expansive pre-clinical examination of ATRA, especially in conjunction with TLR3 ligands and possibly other adjuvants, to establish the safety and efficacy of ATRA for FLC clinical trials.
ORGANISM(S): Homo sapiens
PROVIDER: GSE224888 | GEO | 2023/02/13
REPOSITORIES: GEO
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