2022 World Conference on Lung Cancer (Posters)-P2.10-01. Transcriptional Diversity of Emerging Cell Populations in Refractory Small Cell Lung Cancer Biopsies and Xenografts

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This study explores the transcriptional diversity of emerging cell populations in refractory small cell lung cancer (SCLC). SCLC is known for its rapid onset of platinum resistance, and the mechanisms underlying this resistance are not well understood due to limited tissue samples from relapsed patients. The researchers used liquid biopsies from SCLC patients to generate circulating tumor cell-derived xenograft (CDX) models, which mimic patient tumor genomics and response to platinum chemotherapy. They focused on drug-tolerant persister cells, which exhibit senescence-like dormancy but can re-enter the cell cycle.<br /><br />The study found that emerging populations expressing resistance-associated pathways represent unique drug-resistant persister cell populations responsible for increased intratumoral heterogeneity, therapeutic resistance, and eventual relapse. Non-cycling cells were enriched in epithelial-mesenchymal transition (EMT) and inflammatory response pathways, while cycling cells showed abundance in E2F targets and DNA repair pathways.<br /><br />The researchers analyzed single-cell RNA sequencing data from relapsed SCLC patient core needle biopsies and identified different cell populations based on molecular subtype markers, neuroendocrine and EMT genes, and cell cycle assignment. They also performed droplet-based single-cell transcriptional profiling and removed immune and stromal cells from patient samples for downstream analyses.<br /><br />The study provides insights into the transcriptional complexity underlying SCLC's treatment resistance and highlights the need for combination therapies to target distinct cell populations. The expression of therapeutic targets suggests that non-cycling persister cells may be more sensitive to immune checkpoint blockade, AXL and AURK inhibitors, while cycling cells may respond better to platinum chemotherapy, epigenetic modifiers, or DNA repair targeted therapies.<br /><br />Overall, the findings emphasize the importance of maximizing and maintaining the initial response in platinum-sensitive SCLC tumors and shed light on potential therapeutic strategies for overcoming treatment resistance in SCLC.

Asset Subtitle

C. Allison Stewart, United States

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Speaker C. Allison Stewart, United States

Topic Small Cell Lung Cancer and Neuro-endocrine Tumours

Keywords

transcriptional diversity

emerging cell populations

refractory small cell lung cancer

liquid biopsies

drug-tolerant persister cells

intratumoral heterogeneity

single-cell RNA sequencing

molecular subtype markers

combination therapies

treatment resistance