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. 2021 Jan 5;10(1):8. doi: 10.1038/s41389-020-00292-w

Fig. 6. Combined inhibition of PI3K/mTOR and STAT3 activity significantly inhibits the growth of tumor xenografts.

Fig. 6

Growth curve of A HGC-27 and B MDA-MB-436 xenografts in mice treated with BEZ235 (30 mg/kg) and/or Stattic (3.75 mg/kg) for 20 days. The relative tumor volumes measured every 3 days are plotted. Error bars represent means ± SD (n = 6 mice per group). *P < 0.05. C Representative images of living nude mice injected with HGC-27 cells treated with BEZ235, or Stattic, or BEZ and Stattic or DMSO as indicated (upper panel). Stripped tumors are shown (lower panel). D Schematic representation of feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells. Inhibition of the PI3K/AKT/mTOR signaling pathway led to the feedback activation of STAT3, which attenuated the anti-proliferative effects of PI3K/AKT/mTOR inhibitors in the PTEN-deficient cancer cells. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. The reactivated STAT3 limits the repression of PI3K/AKT/mTOR inhibitors on PTEN-deficient tumor growth.