Apart from primary resistance, secondary (also known as acquired) resistance after initial tumor regression has been reported in patients with RCC.[8] Alternative activation of the PI3K/AKT/mTOR signaling pathway after long‐term therapy is believed to play a critical role in TKI resistance in RCC by increasing HIF and VEGF levels and promoting angiogenesis.[27] Factors promoting AKT pathway activation include interleukin‐6 (IL‐6)[28] and interleukin‐8 (IL‐8).[29] Treatment with IL‐6[30] or IL‐8[31] neutralizing antibodies was found to avoid TKI resistance in RCC. This evidence concerns the gene AKT1 and renal cell carcinoma.