Although genetic mechanisms of resistance to BCR inhibitors in CLL are well‐known, it remains elusive whether non genetic adaptation mechanisms might exist. We focused on the possible role of Akt pathway as PI3K‐Akt activation is the only known factor that rescues the apoptosis induced by BCR deletionin mature Bcells in mouse models. We performed transcriptome profiling (Illumina) and analyzed samples obtained from CLL patients before andduring ibrutinib or idelalisib therapy (1–12weeks of therapy, n=70 patients with 194samples) and performed gene editing in MEC1 cells to reveal the functional role of FoxO1/Rictor.