AKT inhibition leads to the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs), including HER3, IGF-1R, and insulin receptor. This effect is partly due to mTORC1 inhibition and partly due to FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback, activating RTK signaling, which may reduce their antitumor activity. In tumors where AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone. The PI3K-AKT-mTOR pathway is frequently hyperactivated in cancer due to mutations or amplifications in receptor tyrosine kinases, or mutations in pathway components. Tumors with PTEN or PIK3CA mutations or HER2 amplification are dependent on PI3K-AKT-mTOR signaling. Rapamycin, an inhibitor of mTORC1, relieves mTORC1-dependent feedback inhibition of IGF1 receptor signaling, leading to activation of PI3K-AKT signaling. AKT inhibition induces the expression and phosphorylation of HER3, IGF-1R, and insulin receptor. This is mediated by FOXO-dependent activation of receptor expression. AKT inhibition also induces the phosphorylation of multiple RTKs, including HER3, FLT-3, HER4, EphA7, MSPR, insulin receptor, IGF-1R, FGFR3, and FGFR1. These effects are observed in various tumor models, including breast, lung, and ovarian cancers. AKT inhibition induces the expression of HER3, IGF-1R, and insulin receptor, which is not dependent on HER kinase activity. Inhibition of AKT leads to the upregulation of RTK expression and phosphorylation, which is mediated by FOXO transcription factors. FOXO knockdown reduces RTK expression and phosphorylation. Combined inhibition of AKT and HER1/2 kinases is effective in vivo, leading to tumor regression. This suggests that feedback inhibition of RTK signaling by AKT inhibition can be overcome by combining AKT inhibitors with HER kinase inhibitors. These findings highlight the importance of understanding feedback mechanisms in the PI3K-AKT pathway for the development of effective cancer therapies.AKT inhibition leads to the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs), including HER3, IGF-1R, and insulin receptor. This effect is partly due to mTORC1 inhibition and partly due to FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback, activating RTK signaling, which may reduce their antitumor activity. In tumors where AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone. The PI3K-AKT-mTOR pathway is frequently hyperactivated in cancer due to mutations or amplifications in receptor tyrosine kinases, or mutations in pathway components. Tumors with PTEN or PIK3CA mutations or HER2 amplification are dependent on PI3K-AKT-mTOR signaling. Rapamycin, an inhibitor of mTORC1, relieves mTORC1-dependent feedback inhibition of IGF1 receptor signaling, leading to activation of PI3K-AKT signaling. AKT inhibition induces the expression and phosphorylation of HER3, IGF-1R, and insulin receptor. This is mediated by FOXO-dependent activation of receptor expression. AKT inhibition also induces the phosphorylation of multiple RTKs, including HER3, FLT-3, HER4, EphA7, MSPR, insulin receptor, IGF-1R, FGFR3, and FGFR1. These effects are observed in various tumor models, including breast, lung, and ovarian cancers. AKT inhibition induces the expression of HER3, IGF-1R, and insulin receptor, which is not dependent on HER kinase activity. Inhibition of AKT leads to the upregulation of RTK expression and phosphorylation, which is mediated by FOXO transcription factors. FOXO knockdown reduces RTK expression and phosphorylation. Combined inhibition of AKT and HER1/2 kinases is effective in vivo, leading to tumor regression. This suggests that feedback inhibition of RTK signaling by AKT inhibition can be overcome by combining AKT inhibitors with HER kinase inhibitors. These findings highlight the importance of understanding feedback mechanisms in the PI3K-AKT pathway for the development of effective cancer therapies.