Abstract A031: Deciphering the transcriptomic landscape of AKT isoforms and its prognostic impact in patients with lung adenocarcinoma


 AKT kinase is a regulator of several crucial biological functions including metabolism, cell cycle progression and proliferation. Its three isoforms, namely AKT1, AKT2 and AKT3, although they display significant similarities in their sequences, their functions largely differ and often antagonize each other. In the context of human cancer, several studies have previously demonstrated that each three of the AKT isoforms often act as oncogenes or tumor suppressors in the same type of cancer, and especially in lung adenocarcinoma (LUAD). These differences could be attributed to the plethora of different targets and pathways that they directly regulate through phosphorylation or indirectly through different intermediate effectors. One of these targets and pathways can be the regulation of transcription. Based on recent reports, several transcription factors can be directly phosphorylated by AKT kinase in human cancer, globally changing their chromatin occupancy and transcriptional landscape, thus altering transcription regulation. Nevertheless, a comprehensive analysis of the impact of each AKT isoform on transcription regulation and transcription factor enrichment in lung adenocarcinoma was yet to be performed. Here, we were willing to elucidate the genome-wide transcriptional landscape, driven by each AKT isoform, and its prognostic effect in patients with lung adenocarcinoma. To this extent, we utilized Next-Generation Sequencing data from The Cancer Genome Atlas (TCGA) to identify the transcriptomic changes related with the expression of each isoform in LUAD patients. Gene Set Enrichment Analysis revealed enrichment of unique pathways between the three isoforms. In parallel analysis, Transcription Factor enrichment and ATAC-Seq analysis from the same LUAD patients revealed a unique set of transcription factors that are differentially enriched between each AKT isoform group. More importantly, clinical and survival analysis revealed that the top 50 Differentially Expressed Genes (DEG), ranked by q-value, for each isoform correlated with poor overall survival, prognosis free survival, acting as potential prognostic factor in patients with LUAD. In addition, by analyzing publicly available LUAD datasets, through Gene Expression Omnibus (GEO), we demonstrate that the same gene signature is also enriched in relapsing patients. Collectively, our atlas of AKT isoform-mediated transcriptomic landscapes establishes a role of the AKT isoforms in the regulation of transcription by governing transcription factor occupancy in target genes. Given the lack of isoform specific AKT inhibitors, the deep knowledge of the transcriptional landscape driven by each isoform in human lung adenocarcinoma, can open new avenues on the design of precision-medicine markers and therapeutics that can preserve the normal AKT functions, while targeting the oncogenic pathways that these isoforms regulate.
 Citation Format: George Laliotis, Pauline Lin. Deciphering the transcriptomic landscape of AKT isoforms and its prognostic impact in patients with lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A031.