Biophysical characterization of DNAJB1‐PRKACA in Fibrolamellar Hepatocellular Carcinoma

Abstract

Fibrolamellar Hepatocellular Carcinoma (FL‐HCC) has historically been described as a rare and usually fatal pediatric liver cancer that almost exclusively affects adolescents and young adults without a history of underlying liver diseases. Occurring on a healthy background, FL‐HCC's lack of readily recognizable symptoms impedes early diagnosis and timely medical intervention that can prevent tumor's progression to more advanced and metastatic stages. Unfortunately, FL‐HCC is refractory to typically applicable curative regimens in traditional liver cancer such as radiation or chemotherapies, leaving surgical removal the only therapeutic mainstay. However, this approach is still unable to mitigate a 50% reoccurrence rate within 10–33 months.A recent identification of a recurrent chimeric fusion between the catalytic subunit alpha (PRKACA) of protein kinase A, and the J‐domain of the heat shock protein 40 (DNAJB1) in virtually all patients marks an important milestone for the study of FL‐HCC's molecular pathogenesis. The DNAJB1‐PRKACA is central in several ongoing FL‐HCC studies as the primary tumorigenic driver.We are performing a biophysical characterization of the chimera versus the wild‐type protein kinase A. For example, Circular Dichroism is being used to monitor the secondary structure of the chimera in comparison to PRKACA. Differences in thermodynamics and kinase activity due to the J‐domain's fusion in DNAJB1‐PRKACA chimera may modify the protein's interaction with its downstream phosphorylation targets, therefore changing protein kinase A's signaling network implicated in FL‐HCC development. Analysis on changes in the chimera's phosphorylation network relative to the wild‐type protein will provide a crucial insight into FL‐HCC pathogenesis, promoting the development of highly efficacious chemotherapies in treating this disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.