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. Author manuscript; available in PMC: 2014 Jul 31.
Published in final edited form as: Nat Rev Drug Discov. 2014 Feb;13(2):140–156. doi: 10.1038/nrd4204

Figure 4. Rationale for BCL2 antagonist combination.

Figure 4

The balance of pro-survival and proapoptotic BCL2 family members at the mitochondria is a primary factor controlling cell survival versus apoptosis. PI3K/AKT/mTOR signaling suppresses expression and activity of multiple pro-apoptotic proteins (i.e. BAD, BIM, PUMA, and death receptors) and can increase expression of pro-survival factors (MCL-1). However, PI3K/AKT/mTOR inhibition does not necessarily tip the balance towards apoptosis. Combining with small molecule antagonists of pro-survival proteins (BCL2, BCL-XL) increases mitochondrial “priming” for death, lowering the threshold for apoptosis induction by PI3K/AKT/mTOR inhibitors.

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