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.
Keywords: cancer; hepatobiliary cancer; pharmacology.
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