Mcl-1 is a unique antiapoptotic Bcl2 family
protein that functions as a gatekeeper in manipulating apoptosis and survival in
cancer cells. Akt is an oncogenic
kinase that regulates multiple cellular functions and its activity is significantly elevated in human
cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting
lung cancer cell growth. Depletion of endogenous Mcl-1 from human
lung cancer cells using CRISPR/Cas9 or Mcl-1
shRNA significantly decreased Akt activity, leading to suppression of
lung cancer cell growth in vitro and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the
pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and
kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in
tumor tissues from patients with
non-small cell lung cancer. Using the Mcl-1-binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of
lung cancer in vitro and in vivo. By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of
lung cancer. SIGNIFICANCE: These findings indicate that targeting Mcl-1/Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for
cancer treatment.