FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML

Abstract

Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.

miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models

“…Also in this case, analysis of FOXM1 in Hep3B cells revealed a reduction of phosphorylation and amount of FOXM1 protein in samples treated with palbociclib, both as a single agent and in combination with miR-199a-3p ( Figure 2 C). As FOXM1 activation is also AKT-dependent, 29 , 30 inhibition of FOXM1 was also mediated by miR-199a-3p, as we previously reported 15 ( Figure 2 C).

Figure 2 miR-199a-3p increased palbociclib efficacy on human HCC cells in vitro and in vivo (A) Hep3B cells were transduced with an Adeno Associated Virus expressing miR-199a-3p (AAVV-199) or with a control AAVV (AAVV-CTRL) at MOI = 100.

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“…In fact, its lack of phosphorylation by CDK4/6 promotes its degradation and inhibition of its activity. Furthermore, inhibition of FOXM1, which is also activated via the AKT pathway, 29 , 30 can be at the same time sustained by miR-199a-3p.…”

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

“…Therefore, CD44 is a potential therapeutic target to resensitize AML cells to venetoclax. Inactivation of FOXM1, an important protein in cancer development and chemoresistance [ 64 ], as part of a FOXM1-AKT-positive regulation circuit, effectively sensitizes venetoclax-resistant AML cells [ 147 ], also making FOXM1 an interesting therapeutic target to combine with targeting BCL-2.…”

Drug Resistance Mechanisms of Acute Myeloid Leukemia Stem Cells

“…It was found that GLI1 can promote AML cell proliferation directly through PI3K signaling pathway and can be reversed by AKT inhibitors ( 66 ). AKT can enhance FOXM1 expression and form a positive feedback to enhance venetoclax resistance in FLT3 wild-type AML ( 67 ). Therefore, FOXM1 inhibitors may be a promising therapeutic strategy due to their dual signaling pathway regulations.…”