AKT inhibitor capivasertib reverses EVI1‐driven resistance to venetoclax in acute myeloid leukaemia

Acute myeloid leukaemia (AML) with MDS1 and EVI1 complex locus (MECOM) rearrangement is recognized by the World Health Organization as a distinct entity characterized by poor prognosis and aggressive disease progression. This rearrangement evokes aberrant ecotropic viral integration site 1 (EVI1) overexpression, which enhances leukaemic stem cell self-renewal and drives chemoresistance. However, the mechanisms by which EVI1 contributes to venetoclax resistance remain unclear. In this study, patients with AML were stratified into the EVI1-high and EVI1-low groups based on transcript levels. The EVI1-high subgroup exhibited significantly inferior clinical outcomes and reduced complete remission rates following chemotherapy or venetoclax-based regimens. Meanwhile, we demonstrated that elevated EVI1 expression confers resistance to venetoclax by stabilizing myeloid cell leukaemia 1 (MCL-1) through activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in vitro. Mechanistically, elevated EVI1 levels were associated with increased phosphorylation of MCL-1 at threonine 163 (T163pMCL-1), thereby stabilizing MCL-1 by attenuating its ubiquitin-proteasome-mediated degradation. Importantly, cotreatment with venetoclax and the clinically available AKT inhibitor capivasertib effectively restored sensitivity in both cell lines and patient-derived primary AML samples with high EVI1 expression. Overall, our findings reveal a novel molecular mechanism underlying EVI1-mediated venetoclax resistance through PI3K/AKT-driven MCL-1 stabilization and suggest a combination strategy involving AKT inhibition as a promising approach for overcoming therapeutic resistance in this high-risk AML subset.