The study investigates the role of AKT inhibition in relieving feedback suppression of receptor tyrosine kinases (RTKs) in cancer cells. The authors found that AKT inhibition induces the expression and phosphorylation of multiple RTKs, including HER3, IGF-1R, and the insulin receptor, in a wide spectrum of tumor types. This induction is partly due to mTORC1 inhibition and partly due to FOXO-dependent activation of receptor expression. The relief of feedback suppression by AKT inhibition may attenuate the antitumor activity of PI3K-AKT inhibitors. However, combined inhibition of AKT and HER kinase activity is more effective in tumors where AKT suppresses HER3 expression. The findings suggest that targeting both AKT and RTKs may enhance the therapeutic efficacy of anti-cancer treatments.The study investigates the role of AKT inhibition in relieving feedback suppression of receptor tyrosine kinases (RTKs) in cancer cells. The authors found that AKT inhibition induces the expression and phosphorylation of multiple RTKs, including HER3, IGF-1R, and the insulin receptor, in a wide spectrum of tumor types. This induction is partly due to mTORC1 inhibition and partly due to FOXO-dependent activation of receptor expression. The relief of feedback suppression by AKT inhibition may attenuate the antitumor activity of PI3K-AKT inhibitors. However, combined inhibition of AKT and HER kinase activity is more effective in tumors where AKT suppresses HER3 expression. The findings suggest that targeting both AKT and RTKs may enhance the therapeutic efficacy of anti-cancer treatments.