Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

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

Harnessing well-characterized inhibitors of some of these genes may represent a potentially expedient avenue for new FLC therapeutics. One notable example is an inhibitor of CA12, SLC-0111, currently in clinical trials for metastatic pancreatic cancer (see below). Most of the genes we identified here are not currently targeted by drugs or inhibitors; nonetheless, alternative strategies exist to target cells uniquely expressing these genes. Drugs conjugated to antibodies or aptamers that can bind to cell surface proteins that are specific to cells of interest, such as SLC16A14 in FLC cells, represent an emerging strategy for targeting tumor cells. Examination of SLC16A14 expression in the Genotype-Tissue Expression (GTEx) database demonstrated substantially higher expression in FLC tumors than any other normal tissue, indicating that it may be a useful molecular beacon for such approaches. For non-cell surface proteins, this method can be modified by engineering T-cells that recognize the major histocompatibility complex (MHC) class I presenting specific peptides from the protein of interest. Leveraging the knowledge gained in this study to develop new targeted therapeutic approaches remains an important goal.