Hotspots of Aberrant Enhancer Activity in Fibrolamellar Carcinoma Reveal Candidate Oncogenic Pathways and Therapeutic Vulnerabilities

• DOI: 10.1016/j.celrep.2020.03.073
• Publication Date: 2020-04-14T14:59:34Z
• Authors: Timothy A. Dinh; Ramja Sritharan; F. Donelson Smith; Adam B. Francisco; Rosanna K. Ma; Rodica P. Bunaciu; Matt Kanke; Charles G. Danko; Andrew P. Massa; John D. Scott; Praveen Sethupathy
• Keywords: Candidate gene; Viability assay

Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit distinct gene expression profile, the chromatin regulatory landscape and genes most critical for tumor cell survival remain unclear. Here, we use run-on sequencing to discover ∼7,000 enhancers 141 enhancer hotspots activated in relative nonmalignant liver. Bioinformatic analyses reveal aberrant ERK/MEK signaling candidate master transcriptional regulators. We also define strongly associated with of activity, including CA12 SLC16A14. Treatment models inhibitors or SLC16A14 independently reduce viability and/or significantly enhance effect MEK inhibitor cobimetinib. These findings highlight molecular targets drug development, as well combination approaches.