Figure 1. Paradoxical activation of ERK occurs after sorafenib treatment in BRAF^WT HCC cells.

(a) In vitro sensitivity of human and murine HCC cells to clinically relevant doses of sorafenib: The IC₅₀ values indicate that JHH-7 and SK-Hep-1 cells are more sensitive (2.26 μM and 0.5 μM, respectively), while most human HCC cell lines are quite resistant (IC₅₀ of 6.4 μM for SNU-423 cells; 4.75 μM for HLF cells; 4.70 μM for Hep3B cells; 3.82 μM for SNU-449 cells). Similarly, murine HCC1 cells are resistant to sorafenib at these doses (n = 6). (b) Rapid CRAF and ERK activation in BRAF^WT HCC cells but not in BRAF^V600 HCC cells (SK-Hep-1) after sorafenib treatment. All human and murine HCC cell lines tested showed down-regulation of p38MAPK activity after sorafenib treatment. (c) Sorafenib treatment increased ERK activity in orthotopic xenograft HCCs. (d) Spontaneously arising HCCs in Mst1^−/−Mst2^Flox/- transgenic mice (e) and chemically induced HCCs in mice treated with CCl₄ for 28 weeks. (f) CRAF and ERK activation is rapid in Hep3B cells after exposure to PLX4720 and sorafenib. (g) Transactivation of RAF dimers occurred in Hep3B cells (HCC-1 cells) treated with 2 uM sorafenib for 1 h.