2023 World Conference on Lung Cancer (Posters)-EP02.01. Novel Therapeutic Vulnerabilities in SOX2-dependent Squamous Cell Lung Cancer

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This study aimed to investigate the relevance of a truncated isoform of the receptor tyrosine kinase TrkB, called TrkB.T1, in squamous cell lung cancer (LUSC) that is dependent on the lineage-survival oncogene and transcription factor SOX2. The researchers analyzed RNA-Seq data from the TCGA LUSC project to identify differentially expressed genes between SOX2-high and SOX2-low tumors. They then analyzed the expression of different isoforms of the TrkB receptor in vitro and tested TrkB inhibitors in dose-response studies. The necessity of isoform-specific deregulation was assessed through knockdown and knockout experiments. <br /><br />The study found that NTRK2, the gene encoding TrkB, was strongly correlated with SOX2 expression in LUSC patient samples. However, TrkB inhibitors with clinical activity in lung adenocarcinoma had no impact on SOX2-dependent squamous cell lines. The researchers discovered that TrkB.T1 is the predominant isoform in LUSC and other squamous cancers. This isoform lacks the intracellular domain targeted by TrkB inhibitors, explaining their lack of efficacy. The study also showed that NTRK2 expression is upregulated in a novel in vitro model of SOX2-dependent early LUSC. SOX2 was found to be a transcriptional target of SOX2 in this model, and deregulated SOX2 preferentially upregulated the TrkB.T1 isoform. Knockdown of SOX2 reduced the expression of TrkB.T1 in squamous cell lines.<br /><br />In conclusion, TrkB.T1 is identified as a potential novel therapeutic vulnerability in SOX2-dependent LUSC. The study suggests that specific silencing of TrkB.T1 could reduce cell population expansion in squamous cell lines. These findings provide insights into the molecular mechanisms underlying SOX2-dependent LUSC and offer a promising target for future therapeutic interventions.

Asset Subtitle

Daniel Kottmann

Meta Tag

Speaker Daniel Kottmann

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

TrkB.T1

receptor tyrosine kinase

TrkB

squamous cell lung cancer

LUSC

lineage-survival oncogene

SOX2

RNA-Seq data

differentially expressed genes

TrkB inhibitors