E2F-Driven Proliferative Transcription Characterizes an MK-2206-Sensitive AML State and Is Suppressed Following AKT Inhibition

Background: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy in which dysregulated survival, proliferation, and metabolic signaling contribute to treatment resistance. The PI3K/AKT/mTOR pathway is frequently implicated in leukemic cell survival, making AKT inhibition a potential therapeutic strategy. This study aimed to identify transcriptomic features associated with sensitivity to MK-2206, a selective allosteric AKT inhibitor, in AML.

Methods: Publicly available pharmacogenomic and transcriptomic datasets were integrated to characterize molecular features associated with MK-2206 response. Baseline gene-expression profiles from six AML cell lines were analyzed with MK-2206 IC50 values and classified as sensitive or resistant using a three-versus-three comparison. Differential expression analysis was performed between sensitive and resistant cell lines, while GSE172189 was used to assess transcriptional changes following MK-2206 exposure. Baseline and treatment-associated differentially expressed genes were integrated to identify overlapping MK-2206-associated genes. A stricter fold-change threshold defined a 15-gene sensitivity-associated subset. Functional enrichment, gene set enrichment analysis, and network analysis were subsequently performed.

Results: Integration identified 162 overlapping MK-2206-associated genes, from which a stricter threshold defined a 15-gene subset that distinguished sensitive from resistant AML cell lines. Network analysis revealed functional associations with energy metabolism, DNA replication, cell-cycle regulation, chromosomal organization, and vesicular trafficking, with YWHAE emerging as a highly connected node. Functional annotation of the broader gene set implicated Rho GTPase signaling, apoptosis, interferon response, DNA repair, and cell-cycle checkpoint regulation. Gene set enrichment analysis demonstrated suppression of MYC/E2F-associated proliferation, DNA replication, DNA repair, G2/M checkpoint, mitotic spindle, and oxidative phosphorylation programs following MK-2206 exposure, alongside activation of stress-response pathways including unfolded protein response and p53-associated DNA-damage signaling.

Conclusion: MK-2206 sensitivity in AML appears to reflect a broader transcriptional state involving proliferative, metabolic, genome-maintenance, apoptotic, interferon-related, and cellular stress-response programs rather than dependence on a single gene.