Apoptosis induction is considered to require antagonism of all prosurvival Bcl 2 family members expressed in a particular mobile by BH3 only proteins. We found that the N RAF mutant cyst cells that were BIX01294 most resistant to MEK inhibitor induced apoptosis expressed the highest levels of Bcl 2 and the cheapest levels of Bim. Consequently, dysfunctional tumor cell-killing might be a consequence of incomplete neutralization of Bcl 2. We and the others have previously shown that BH3 mimetics may potently collaborate with the EGF receptor tyrosine kinase inhibitor gefitinib, and the BCR ABL tyrosine kinase inhibitor imatinib, within the treatment of cyst cells transformed by these oncogenic kinases. Shutdown of the MEK ERK1/2 pathway was found to be critical for imatinib induced as well as gefitinib induced tumor cell-killing. Accordingly, in the present research we observed that ABT 737 erthropoyetin synergized with MEK inhibition within the killing of B RAF mutant tumefaction cells, even those that spontaneously or through experimental modification expressed abnormally high levels of Bcl 2 or reduced levels of Bim. Previous work showed that MEK inhibitors may cause growth arrest, although not substantial regression, of xenografted B RAF mutant tumors in nude mice. Here, we discovered that the MEK inhibitor PD0325901 synergized with ABT 737 in vivo to cause extended regression of B RAF mutant tumors in nude mice. The tumor growth delay achieved with combination treatment was very significant compared with the consequences seen with PD0325901 alone. Somewhat, these results were achieved with low doses of PD0325901, which created minor growth inhibitory effects when applied alone. In addition, tumors remained susceptible to retreatment with PD0325901 and, even more impressively, to retreatment with the combination of PD0325901 and ABT 737 at the time of cyst relapse, which indicates that extended treatment sessions may be even more efficacious. Others have proposed that dephosphorylation Aurora A inhibitor of Bcl 2 is crucial for the synergistic relationship between MEK inhibition and ABT 737 in the killing of acute myeloid leukemia cells. This seems unlikely in Colo205 cells, since they convey only very low degrees of Bcl 2. Instead, we genuinely believe that ABT 737 liberates Bim and perhaps other BH3 only proteins from Bcl 2 and Bcl xL, thereby allowing efficient neutralization of all prosurvival Bcl 2 family members, including Mcl 1 and potentially A1, in the tumefaction cells. Jointly, studies with tumor cells addicted to 3 different oncogenic kinases BCR ABL, mutated EGF R, and now mutated B RAF show that their killing by certain Figure 5 Addition of ABT 737 significantly improves the MEK inhibition induced apoptosis of B RAF mutant tumor cells by increasing the binding of Bim to Mcl 1. Colo205 cells were treated with ABT 737 plus 0 or 20 m UO126 or with UO126 plus 0 or 1 m ABT 737.