The direct GSK-3β/4EBP1 pathway, not associated with the PI3K/Akt/mTORC1 pathway, would be an important subcellular intrinsic mechanism for RCC cells to resist mTORC1 inhibition, possibly leading to potential therapeutic limitations in systemic treatment for mRCC patients with rapalogues. The gene discussed is AKT1; the disease is renal cell carcinoma.