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

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This document presents research on the vulnerability of squamous carcinomas with SOX2 deregulation to AKT3 inhibition. SOX2 is a transcription factor that plays a critical role in development and maintenance of airway epithelium. When deregulated, it becomes implicated as an oncogene in squamous lung and esophageal carcinomas. Amplification of 3q, a chromosomal aberration, is common in squamous lung cancer and is associated with the evolution of preinvasive squamous lung cancer. SOX2 is considered the critical target of 3q amplification. However, there are currently no validated targeted therapeutics for SOX2-dependent squamous cancers.<br /><br />To study the molecular action of SOX2 and identify potential therapeutic targets, the authors developed an organotypic (OTC) model system that mimics key genetic lesions found in lung squamous carcinoma. They used RNA-seq and ChIP-seq to analyze the impact of SOX2 deregulation. Using the OTC model, they screened multiple compounds against vulnerabilities in key pathways implicated in squamous carcinoma. They then used RNAi and CRISPR techniques to genetically validate putative targets.<br /><br />The results showed that pan-AKT inhibitors, but not selective AKT1/2 inhibitors, PI3K, or MEK inhibitors, have therapeutic potential in SOX2-dependent bronchial dysplasia. Pan-AKT inhibition prevented the development of dysplastic lesions and also reversed established dysplasia. RNA-seq and ChIP-Seq data revealed that SOX2 deregulation is associated with the upregulation of AKT3. Further experiments showed that squamous carcinoma cell lines with SOX2 dependence were vulnerable to pan-AKT inhibition. Specifically, AKT3 was found to be essential for ongoing survival in colony formation assays and in vivo.<br /><br />Based on these findings, the authors suggest that squamous cancers with SOX2 amplification may be vulnerable to isoform-specific inhibition of AKT3. This research provides valuable insights into potential targeted therapeutic options for SOX2-dependent squamous carcinomas, which currently have no validated treatments.

Asset Subtitle

Wenrui Guo

Meta Tag

Speaker Wenrui Guo

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

squamous carcinomas

SOX2 deregulation

AKT3 inhibition

transcription factor

airway epithelium

oncogene

3q amplification

organotypic model system

therapeutic potential

isoform-specific inhibition