2023 World Conference on Lung Cancer (Posters)-EP02.01. SOX2 Deregulated Squamous Carcinomas Are Vulnerable to AKT3 Inhibition

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Researchers from the University of Cambridge have developed an in vitro organotypic model of early squamous cell lung cancer (SQC) that replicates key genetic events associated with the disease. In this model, they demonstrate a specific vulnerability to pan-AKT inhibition, particularly AKT3. The researchers have linked the putative driving oncogene, SOX2, specifically with AKT3 and show that SQC cell lines with amplified SOX2 are vulnerable to AKT3 inhibition. They believe that this study could lead to a novel biomarker-driven clinical trial in SQC and further refinement of AKT3 as a target. <br /><br />The in vitro organotypic model used in this study allows researchers to screen compounds for chemopreventive efficacy. Through their screening, they found that inhibition of PI3K and MEK1/2 caused potentiation of the dysplastic phenotype, while inhibition of AKT1/2/3 using MK-2206 showed no effect. However, AKT1/2/3 inhibition with AZD5363 resulted in resolution of dysplasia to a monolayer epithelium. The researchers observed similar results with other AKT inhibitors as well. <br /><br />Furthermore, the study revealed that SOX2 directly regulates AKT3 expression. Deregulated SOX2 is associated with elevated AKT3 in clinical specimens, and knocking down AKT3 resulted in a significant loss of colony formation capacity in SOX2 amplified and dependent squamous cell lines. In xenograft models, the dependence of AKT3 in tumorigenesis was also observed. <br /><br />Overall, this study sheds new light on the role of SOX2 in SQC and offers potential avenues for targeted therapy. The researchers are currently developing a clinical trial to further investigate the efficacy of AKT3 inhibition in patients with SQC.

Asset Subtitle

Wenrui Guo

Meta Tag

Speaker Wenrui Guo

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

University of Cambridge

in vitro organotypic model

squamous cell lung cancer

AKT3 inhibition

SOX2

biomarker-driven clinical trial

chemopreventive efficacy

PI3K inhibition

colony formation capacity

targeted therapy