Note: Yuying was selected and funded by the National Cancer Institute's Integrative Cancer Biology Program (ICBP).
The observation that EGFR mutant adenocarcinomas can transform into small cell lung carcinomas after EGFR inhibitor treatment has elucidated a novel mechanism of resistance to subtype-specific therapies. However, the molecular pathways behind this transformation are largely unknown. Surprisingly, we found that overexpression of SOX2, a transcription factor commonly amplified in squamous and small cell lung carcinoma but not in adenocarcinoma, can confer resistance to EGFR inhibition in the context of lung adenocarcinoma. Previous studies have identified SOX2 as a potential lineage-survival oncogene in squamous and small cell lung cancer due to SOX2’s role in pluripotency and cell fate. We hypothesized that SOX2 may induce resistance through transforming lung adenocarcinoma cells to squamous (SQLC) or small cell lung carcinoma (SCLC). To investigate the mechanism of SOX2-induced resistance, we compared gene expression signatures of overexpression of SOX2 or EGFR pathway oncogenes in adenocarcinoma cells using Non-negative Matrix Factorization (NMF) analysis. Results show that SOX2 and EGFR-induced gene signatures share some components. GSEA Gene Set Enrichment Analysis further indicated that the shared component has some commonalities with the neurotrophin pathway, suggesting that SOX2 enhances a certain component of EGFR regulation to create neural characteristics similar to neuroendocrine tumors. Surprisingly, overexpression of SOX2 in EGFR mutant PC-9 cells resulted in the downregulation of the EGFR pathway. We also observed an increase in the SQLC marker p63 with minimal changes in the SCLC marker ascl-1, indicating that SOX2 overexpression results in squamous carcinoma characteristics. Our findings provide mechanistic insight that may be important in understanding and preventing lineage transformation as a resistance mechanism to targeted lung cancer therapies.
PROJECT: Understanding the role of SOX2 in resistance to EGFR inhibition in lung adenocarcinoma
The Broad not only fosters independent thinking, but it also encourages curiosity and collaboration. More importantly, the Broad instilled in me both confidence and humility as a researcher. I am grateful to the Broad for providing me with the mindset and motivation for success.