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Centrosomal Localization of DNAJ-PKAc Fusion Heightens PLK1 Inhibitor Sensitivity in Fibrolamellar Cancer

ABSTRACT: Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumor growth remains enigmatic. Employing an unbiased systems-based approach, we uncovered a new role of DNAJ-PKAc oncoprotein in FLC and identified downstream kinases involved in this process. Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumor growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues. Our findings underscore the role of DNAJ-PKAc in rewiring signaling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250059 | GEO | 2023/12/19

REPOSITORIES: GEO

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Retinoic acid treatment suppresses fibrolamellar carcinoma growth

Project description: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.

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An acquired scaffolding function of the DNAJ-PKAc fusion enhances oncogenesis in Fibrolamellar carcinoma

Project description:Fibrolamellar carcinoma (FLC) is a rare liver cancer. FLC tumors exclusively produce DNAJ-PKAc, a de novo chimeric enzyme consisting of a chaperonin-binding domain fused to the C subunit of protein kinase A. Biochemical analyses of clinical samples reveal that a unique property of DNAJ-PKAc is the ability to recruit heat shock protein 70 (Hsp70). This cellular chaperonin is frequently up-regulated in cancers. Gene-editing of mouse hepatocytes generated disease-relevant AML12DNAJ-PKAc cell lines. Drug-screening discovered Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells. Further analyses indicate that the proto-oncogene AKAP-Lbc is upregulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module. Phosphoproteomic profiling infers that DNAJ-PKAc biases the signaling landscape toward ERK activation and mobilizes other downstream kinase cascades. We propose that the oncogenic nature of DNAJ-PKAc proceeds through an acquired scaffolding function that permits recruitment of Hsp70 and stabilizes ERK signaling.

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DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma

Project description:Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long non-coding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo models of disease. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, an indicator of mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.

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