{
  "abstract": "Background 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 tumour growth remains enigmatic.Objective We sought to determine the protein kinase-mediated signalling networks that drive growth and proliferation in FLC.Design We integrated a combination of newly established preclinical models of FLC and an unbiased polypharmacology-based approach to identify downstream kinases involved in DNAJ-PKAc-mediated FLC cell growth. We validated our findings in multiple patient-derived mouse models and patient tumours.Results 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 tumour growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues.Conclusion Our findings underscore the role of DNAJ-PKAc in rewiring signalling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.",
  "authors": [
    {
      "affiliations": [
        "Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA"
      ],
      "name": "Marina Chan"
    },
    {
      "affiliations": [
        "Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA"
      ],
      "name": "Songli Zhu"
    },
    {
      "affiliations": [
        "Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA"
      ],
      "name": "Manabu Nukaya"
    },
    {
      "affiliations": [
        "Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA"
      ],
      "name": "Luisa T Ferreira"
    },
    {
      "affiliations": [
        "Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA"
      ],
      "name": "Sean M Ronnekleiv-Kelly"
    },
    {
      "affiliations": [
        "Department of Surgery, University of Washington, Seattle, Washington, USA"
      ],
      "name": "Kimberly J Riehle"
    },
    {
      "affiliations": [
        "Department of Pharmacology, University of Washington, Seattle, Washington, USA"
      ],
      "name": "John D Scott"
    },
    {
      "affiliations": [
        "Department of Surgery, University of Washington, Seattle, Washington, USA"
      ],
      "name": "Raymond S Yeung"
    },
    {
      "affiliations": [
        "Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA",
        "Department of Pharmacology, University of Washington, Seattle, Washington, USA"
      ],
      "name": "Taranjit S Gujral"
    }
  ],
  "title": "DNAJ-PKAc fusion heightens PLK1 inhibitor sensitivity in fibrolamellar carcinoma",
  "uid": "5b88bbab-1643-565d-bf25-535ebb807109"
}