Suppression of AKT Phosphorylation Restores Rapamycin-Based Synthetic Lethality in SMAD4-Defective Pancreatic Cancer Cells

mTOR has been implicated in survival signals for many human cancers. Rapamycin and TGF-beta synergistically induce G(1) cell-cycle arrest in several cell lines with intact TGF-beta signaling pathway, which protects cells from the apoptotic effects of rapamycin during S-phase of the cell cycle. Thus, rapamycin is cytostatic in the presence of serum/TGF-beta and cytotoxic in the absence of serum. However, if TGF-beta signaling is defective, rapamycin induced apoptosis in both the presence and absence of serum/TGF-beta in colon and breast cancer cell lines. Because genetic dysregulation of TGF-beta signaling is commonly observed in pancreatic cancers-with defects in the Smad4 gene being most prevalent, we hypothesized that pancreatic cancers would display a synthetic lethality to rapamycin in the presence of serum/TGF-beta. We report here that Smad4-deficient pancreatic cancer cells are killed by rapamycin in the absence of serum; however, in the presence of serum, we did not observe the predicted synthetic lethality with rapamycin. Rapamycin also induced elevated phosphorylation of the survival kinase Akt at Ser473. Suppression of rapamycin-induced Akt phosphorylation restored rapamycin sensitivity in Smad4-null, but not Smad4 wild-type pancreatic cancer cells. This study shows that the synthetic lethality to rapamycin in pancreatic cancers with defective TGF-beta signaling is masked by rapamycin-induced increases in Akt phosphorylation. The implication is that a combination of approaches that suppress both Akt phosphorylation and mTOR could be effective in targeting pancreatic cancers with defective TGF-beta signaling. (C)2013 AACR.