Abstract B127: Evaluating PRKACA as a therapeutic target for Fibrolamellar Carcinoma

Introduction: Fibrolamellar Carcinoma (FLC) is a rare primary liver malignancy, affecting children and young adults without chronic liver disease. FLC tumors are largely resistant to chemotherapy, making the identification of effective treatment options urgently needed. Recent genomic data strongly suggest that DNAJB1-PRKACA kinase fusions are the drivers of the vast majority of FLC cases. However, it has not been assessed whether FLC tumors remain dependent on DNAJB1-PRKACA expression and whether PRKACA inhibition could be a therapeutic approach for FLC. Here we summarize the preclinical evaluation of PRKACA as a potential therapeutic target for FLC. Methods: We established a xenograft model from a FLC- patient and then developed inducible PRKACA shRNA cell lines from this model. We also designed potent tool compounds that selectively inhibit the PRKACA protein to assess PRKACA as a potential therapeutic target for FLC. Results: We characterized a patient-derived xenograft (PDX) model of FLC (LI5132) and confirmed DNAJB1-PRKACA fusion expression and constitutive PRKACA pathway activation measured by phospho-VASP. The model also shows fibrolamellar type histology by HE 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B127. doi:10.1158/1535-7163.TARG-19-B127