Proposed mechanistic model by which dual disruption of PI3K/Akt and MEK/ERK1/2 pathways induces apoptosis. Dual disruption of the MEK/ERK1/2 and PI3K/Akt pathways results in Bim accumulation, most likely through enhanced transcription and diminished degradation by the proteasome system as a consequence of Bim dephosphorylation. In addition, this treatment also diminishes Mcl-1 protein levels through a caspase-independent process, leading to Bim and Bak release from Mcl-1. These events may involve 2 possible mechanisms: (1) direct activation of Bax by accumulation of Bim; and (2) binding of Bim to Bcl-2 and Bcl-x_L, thereby displacing Bax and Bak from these antiapoptotic proteins. Both mechanisms lead to Bax and Bak conformational change and activation, mitochondrial outer membrane permeabilization, release of cytochrome c, and other proapoptotic factors, culminating in apoptosis induction.