2024 Hot Topic in Basic & Translational Science: Tolerance & Resistance to Targeted Therapy in NSCLC - Posters-PP01.15: Transcriptional Changes Associated with Tolerance to EGFR Tyrosine Kinase Inhibitors in Mutant EGFR Lung Cancer PDX Models

PP01.15: Transcriptional Changes Associated with Tolerance to EGFR Tyrosine Kinase Inhibitors in Mutant EGFR Lung Cancer PDX Models

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The study investigates the transcriptional changes linked to tolerance mechanisms in mutant EGFR lung cancer using patient-derived xenograft (PDX) models. These models evaluated responses to first-generation (erlotinib) and third-generation (osimertinib) EGFR tyrosine kinase inhibitors (TKIs).<br /><br />The research identifies two primary forms of response to TKI treatment: limited response with cytotoxic tolerance, resembling a clinical "stable disease," and a drug-tolerant persister (DTP) response, where small subsets of tumor cells survive the initial cytotoxic effect. These responses are not adequately understood, prompting this study.<br /><br />Four PDX models were developed from patients with EGFR mutations, two from chemotherapy-naive patients and two from post-EGFR TKI treatment patients. Transcriptomic analyses were conducted using bulk RNA methods and single-cell RNA sequencing, revealing differential gene expression and enriched pathways associated with tolerance mechanisms.<br /><br />Key findings include:<br />- Certain models, like PHLC137 and PHLC164, exhibited an initial cytotoxic response that transitioned into a DTP state.<br />- PHLC4672 maintained stable disease characteristics with downregulated proliferation-associated genes.<br />- PHLC4547 displayed resistance without significant transcriptomic differences between treated and untreated tumors.<br /><br />The study's results highlight the activation of survival and stress pathways in DTPs, which extend beyond drug-induced tumor growth arrest mechanisms. These insights contribute to understanding molecular adaptations in response to EGFR TKIs, offering potential targets for overcoming drug tolerance in lung cancer treatment.<br /><br />This research underscores the complexity of cancer drug resistance and the necessity for advanced therapeutic strategies to manage and counter these adaptive responses. The identification of common hallmark pathways in enriched DEGs presents opportunities for further investigation into targeted therapies.

Asset Subtitle

Nhu-An Pham

Keywords

EGFR

lung cancer

transcriptional changes

xenograft models

tyrosine kinase inhibitors

drug-tolerant persister

transcriptomic analyses

gene expression

cancer drug resistance

targeted therapies