WCLC 2025 - Posters & ePosters-P3.03.15 Investigating Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer Through High Resolution Transcriptomics

P3.03.15 Investigating Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer Through High Resolution Transcriptomics

Back to course

Pdf Summary

This study by Eva Cabrera San Millan investigates mechanisms of resistance to Osimertinib (Osi) in Epidermal Growth Factor Receptor (EGFR)-mutated Non-Small Cell Lung Cancer (NSCLC), the most common lung cancer type. Although Osi is the standard treatment for patients harboring key EGFR mutations (T790M/L858R, L858R, exon 19 deletion), acquired resistance invariably develops, leading to treatment failure. The research focuses on understanding tumor microenvironment and cellular changes that contribute to this resistance.<br /><br />Using both in vitro cell cultures and genetically engineered mouse models (GEMMs) representing the three common EGFR mutations, the study combines 3D imaging, RNA sequencing, spatial transcriptomics, and single-cell RNA sequencing to analyze molecular and cellular alterations linked to Osi resistance.<br /><br />Key in vitro findings show that Osi-resistant (OsiR) H1975 cells display increased migration ability, altered nuclear morphology, and mitochondrial fragmentation compared to Osi-sensitive (OsiS) counterparts, indicating mitochondrial dynamics might underlie resistance. Transcriptomic analysis reveals metabolic reprogramming favoring glycolysis in resistant H1975 cells. PC9 cells did not show differences between OsiR and OsiS states. <br /><br />In vivo, the team successfully generated Osi-sensitive and Osi-resistant GEMMs for EGFRTL and EGFRD19 mutations and is progressing with the EGFRLR model. Tumor monitoring via microCT and high-resolution transcriptomics identified transcriptional cell clusters and tumor-specific epithelial cells interacting with the tumor microenvironment.<br /><br />The study advances understanding of resistance mechanisms to EGFR-targeted therapy in NSCLC and highlights metabolic and mitochondrial changes as potential contributors. These findings could inform development of personalized therapeutic strategies to overcome Osi resistance, addressing a major clinical challenge for patients with EGFR-mutant NSCLC.

Asset Subtitle

Eva Cabrera San Millan

Meta Tag

Speaker Eva Cabrera San Millan

Topic Tumor Biology – Translational Biology

Keywords

Osimertinib resistance

EGFR-mutated NSCLC

tumor microenvironment

mitochondrial dynamics

metabolic reprogramming

glycolysis

3D imaging

RNA sequencing

genetically engineered mouse models

personalized therapy