AKT1^E17K‐Interacting lncRNA SVIL‐AS1 Promotes AKT1 Oncogenic Functions by Preferentially Blocking AKT1^E17K Dephosphorylation

AKT1^E17K is a gain-of-function mutation that constitutively activates the PI3K-AKT pathway. However, how AKT1^E17K is regulated in cancer pathogenesis remains elusive. Here, RNA immunoprecipitation sequencing (RIP-seq) is performed to interrogate the AKT1^E17K-interacting lncRNAs and identify that SVIL-AS1 preferentially binds to AKT1^E17K rather than AKT1^WT proteins. It is found that SVIL-AS1 enhances AKT1 phosphorylation and downstream signaling. SVIL-AS1 knockdown dramatically inhibits the growth of AKT1^E17K cells in vitro and in vivo. Notably, AKT1 and SVIL-AS1 interaction is AKT1 phosphorylation-dependent. SVIL-AS1 also interacts with PPP2R2A, a subunit of phosphatase PP2A holoenzyme, and blocks the binding of PPP2R2A to AKT1^E17K to prevent AKT1 dephosphorylation. Moreover, AKT1^E17K cells are not effectively inhibited by the allosteric AKT inhibitor, whereas silencing SVIL-AS1 sensitizes AKT1^E17K cells to AKT1 allosteric inhibitor, as well as the PI3Kα inhibitor. In breast cancer tissues, SVIL-AS1 is highly expressed and associated with p-AKT1 level and poor prognosis of patients. Together, the findings discover a novel lncRNA regulator of mutant oncoprotein which preferentially prevents AKT1^E17K dephosphorylation. Targeting SVIL-AS1 may help to improve the responses to inhibitors of the PI3K-AKT pathway, especially in AKT1^E17K mutant tumors.