MAPK signaling network model simulations predict synergistic activity between cobimetinib and GDC-0994.

<p>(<b>a</b>) MAPK signaling model schematic, wherein the system input Grb2-SOS induces catalysis of Ras-GDP to Ras-GTP, which then catalyzes a phosphorylation cascade from BRAF/CRAF dimers via MEK to ERK, with ppERK as the system output. Three canonical negative feedback mechanisms are considered; inhibitory phosphorylation of MEK and CRAF by ppERK, DUSP-mediated ERK de-phosphorylation, and SPRY-mediated inhibition of Grb2-SOS/RAS signaling. (<b>b</b>, <b>c</b>) Fractional cell viability was predicted in the presence of combined doses of two drugs ranging from 1 to 1000 nM in half-log dilution steps to form a 9x9 matrix; Isobolograms show the predicted effect on cell viability at each dose level (grey lines), with blue line showing 70% effect compared to expected effect for Loewe additivity (red line). Combining GDC-0994 with cobimetinib (<b>b</b>) results in deviation from additivity, combining cobimetinib with itself (<b>c</b>) demonstrates that an additive effect conforms to the expected Loewe model.