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.