Increased activity of protein kinase A, even without DNAJB1, is sufficient to cause Fibrolamellar hepatocellular carcinoma

Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC. Primary Human Hepatocytes were transduced with either DNAJB1::PRKACA, ATP1B1::PRKACA, PRKACA or kinase inactive DNAJB1::PRKACA or dsRED.