The HDACI/BH3-mimetic regimen displays activity in vivo which is blocked by Bim shRNA knockdown. (A-B) NOD/SCID-γ mice were subcutaneously inoculated in the flank with (A) 5 × 10⁶ PS-R or (B) U266/shBim cells. Doses of 100 mg/kg ABT-737 and 200 mg/kg SBHA were administrated intraperitoneally individually or in combination (n = 5 per group) 3 days per week. Control animals were administered equal volumes of vehicle. Tumor size was measured by caliper, and volumes were calculated by using the formula (length × width²)/2. (C) A mechanistic model for the roles of Bim in adaptive drug resistance and priming resistant MM cells toward death. Left: BH3 mimetics (eg, ABT-737) simultaneously activate apoptosis and autophagy by releasing Bim and Beclin-1 from Bcl-2, respectively. Whereas the former action is therapeutically beneficial, it is opposed by the latter cytoprotective response (autophagy ON), which raises the cell death threshold and promotes drug resistance. In this setting, Bim downregulation is associated with adaptive resistance to targeted agents such as bortezomib. Right: HDACIs upregulate Bim in MM cells, including those resistant to bortezomib due to Bim downregulation, and thereby reprime them to BH3-mimetic–induced apoptosis. The latter event is related, at least in part, to disruption of cytoprotective autophagy (autophagy OFF) through release of Bcl-2 from Bim and resulting enhanced sequestration of Beclin-1 by Bcl-2. Notably, inhibition of autophagy (eg, by CQ) significantly increases HDACI/BH3 mimetic regimen lethality, particularly in Bim^low MM cells. Thus, loss of Bim expression can contribute to an adaptive form of bortezomib resistance, and a Bim-targeting strategy combining HDACIs, which upregulate Bim, with BH3 mimetics, which release Bim from antiapoptotic Bcl-2 family proteins, may represent an effective approach to this problem.