Unique roles of Akt1 and Akt2 in IGF-IR mediated lung tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The serine-threonine kinase AKT is hyperactivated in various cancers, including lung cancer.
• Current AKT inhibitors in clinical trials target all three AKT isoforms (AKT1-3) indiscriminately.
• The distinct roles of AKT isoforms in cancer remain largely unelucidated.

Purpose of the Study:

• To investigate the specific functions of AKT isoforms in lung tumorigenesis.
• To evaluate the efficacy of isoform-selective AKT inhibition in lung cancer models.

Main Methods:

• Utilized a transgenic mouse model with IGF-IR overexpression to drive lung tumorigenesis.
• Performed loss-of-function studies for Akt1 and Akt2 in the mouse model.
• Conducted RNA sequencing to identify differentially expressed genes in tumors lacking Akt2.
• Assessed cell survival using selective AKT1 and pan-AKT inhibitors in human lung cancer cell lines.

Main Results:

• Loss of Akt1 inhibited lung tumor development, whereas loss of Akt2 enhanced it.
• Lung tumors lacking Akt2 exhibited a dispersed growth pattern instead of discrete nodules.
• RNA sequencing identified five genes (Actc1, Bpifa1, Mmp2, Ntrk2, Scgb3a2) differentially expressed in Akt2-deficient tumors, with known links to human lung cancer.
• A selective AKT1 inhibitor demonstrated greater potency in regulating cell survival than a pan-AKT inhibitor in human lung cancer cell lines.

Conclusions:

• AKT isoforms play divergent roles in lung tumorigenesis.
• Selective inhibition of AKT1 may offer a more effective therapeutic strategy for lung adenocarcinoma compared to pan-AKT inhibition.