Serglycin-ROS axis mediates synergistic lethality of PI3Kγ inhibition and Azacitidine in TP53-mutated AML

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• TP53-mutated acute myeloid leukemia (AML) is an aggressive subtype with limited treatment options.
• The PI3Kγ signaling pathway plays a role in AML pathogenesis.
• Novel therapeutic strategies are needed to improve outcomes for TP53-mutated AML patients.

Purpose of the Study:

• To investigate the synergistic potential of combining PI3Kγ inhibition with Azacitidine (AZA) in TP53-mutated AML.
• To elucidate the molecular mechanisms underlying this combination therapy's efficacy.
• To explore PI3Kγ (PIK3CG/PIK3R5) expression in AML cell lines.

Main Methods:

• Assessed PI3Kγ expression in TP53-mutated and wildtype AML cell lines using CCLE, RT-qPCR, and western blot.
• Evaluated the effects of AZA and the PI3Kγ inhibitor Eganelisib on AML cells in vitro and in vivo.
• Utilized RNA sequencing and siRNA to identify synergistic targets and elucidate mechanisms, focusing on the SRGN-ROS axis.

Main Results:

• TP53-mutated AML exhibits PI3Kγ promoter hypermethylation and reduced PI3Kγ expression.
• AZA selectively activated PI3Kγ signaling in TP53-mutated cells.
• The combination of Eganelisib and AZA demonstrated significant synergy, suppressing proliferation and inducing apoptosis in TP53-mutated AML, and extending survival in xenograft models.
• RNA-seq identified serglycin (SRGN) as a mediator linking AZA-induced changes to ROS-mediated cell death; SRGN knockdown sensitized cells to AZA, and the combination increased ROS levels.

Conclusions:

• PI3Kγ inhibition sensitizes TP53-mutated AML to AZA via a mechanism involving the SRGN-ROS axis.
• This preclinical evidence supports a translatable combinatorial strategy for treating this aggressive AML subtype.
• The combination therapy offers a promising new avenue for patients with TP53-mutated AML.