Overexpression of wild type KRAS increased the IC50 (inhibitory concentration of drug that decreases cell viability to 50%) to crizotinib from 0.16 μM to 1.68 μM (p-value < 0.001) (Figure 4A, ,4G)4G) and NF1 downregulation increased the IC50 to crizotinib from 0.16 μM to 0.75 μM (p-value < 0.001) (Figure 4D, ,4H).4H). Treatment of cells harboring both METex14 and KRAS overexpression with the combination of crizotinib and the MEK inhibitor trametinib in order to block both MET signaling and downstream MAPK pathway signaling restored sensitivity to treatment (crizotinib IC50 of 1.68 μM in the absence of trametinib versus 0.25 μM with trametinib co-treatment, p-value < 0.001) (Figure 4B, ,4G).4G). Similarly, co-treatment of cells harboring both METex14 and NF1 downregulation with both trametinib and crizotinib restored sensitivity to treatment (crizotinib monotherapy IC50 0.75 μM versus 0.18 μM upon addition of trametinib, p-value < 0.001 (Figure 4E, ,4H).4H). The selected trametinib dose modestly reduced but did not eliminate cell growth in the absence of crizotinib (Supplemental Figure S5). Immunoblotting demonstrated sustained Erk phosphorylation despite crizotinib treatment in samples with KRAS overexpression or NF1 downregulation, which was abrogated by the addition of trametinib (Figure 4C, ,4F).4F). In both genomic contexts, combination treatment was associated with increased levels of cleaved PARP, indicative of apoptosis, which was absent with monotherapy (Figure 4C, ,4F4F).
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