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

We next tested whether inhibition of MAPK signaling reduces viability of human FLC tumor cells. First, we derived a primary human FLC cell line from a patient-derived xenograft (PDX) model by optimizing previously described protocols (Dinh et al., 2019; Liu et al., 2017, see Materials and Methods) . Treatment with cobimetinib reduced ERK phosphorylation as expected (Fig. 7G) , and significantly decreased FLC cell viability (Fig. 7H ), but only at higher doses of the drug. This effect was confirmed across three distinct derivations of the FLC cell line (Fig. 7H, Fig. S6B ), each of which was positive for DNAJB1-PRKACA expression. Our results suggest that FLC cells are susceptible to MAPK inhibition, however the doses needed for a cytotoxic effect indicate an intrinsic level of drug resistance in these cells.