Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance
Dinh, T. A.; Sritharan, R.; Smith, F. D.; Francisco, A. B.; Ma, R. K.; Bunaciu, R. P.; Kanke, M.; Danko, C. G.; Massa, A. P.; Scott, J. D.; Sethupathy, P.
Show abstract
Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the causative transcriptional mechanisms remain unclear. Here we used chromatin run-on sequencing to discover approximately 7,000 enhancers and 141 enhancer hotspots activated in FLC relative to non-malignant liver. Detailed bioinformatic analyses revealed aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also defined the genes most strongly associated with aberrant FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduced cell viability and/or significantly enhanced the effect of MEK inhibitor cobimetinib. These findings highlight new molecular targets for drug development as well as novel drug combination approaches.
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