DNAJ-PKAc fusion heightens PLK1 inhibitor sensitivity in fibrolamellar carcinoma
Menée à l'aide de modèles murins et d'échantillons tumoraux issus de patients atteints d'un carcinome fibrolamellaire, cette étude met en évidence un mécanisme par lequel l'oncoprotéine de fusion DNAJ-PKAc, via l'activation de la kinase PLK1, favorise la croissance tumorale
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.
Gut , article en libre accès 2025