Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of cancer that affects primarily teenagers and young adults. FLC tumors are nearly always associated with an intrachromosomal deletion resulting in expression of a fusion protein between the chaperone DNAJ1B and the protein kinase PKA. FLC is challenging to study because of its rarity and limited pre-clinical models. Here we developed a novel transgenic mouse model of FLC. In this model, DNAJ1B-PKA overexpression in the liver of mouse embryos results in perinatal lethality. DNAJ1B-PKA overexpression in the liver of adult mice initiates tumors resembling FLC at low penetrance. Some of these tumors can be serially propagated in 3D cultures and in allografts, including in syngeneic hosts. One such model shows growth inhibition upon treatment with the CDK4/6 inhibitor palbociclib. New pre-clinical models of FLC will provide novel insights into the biology of this rare cancer and may help identify novel therapeutic strategies.

Development of pre-clinical murine models for fibrolamellar hepatocellular carcinoma