Z Gastroenterol 2025; 63(08): e520-e521
DOI: 10.1055/s-0045-1810912
Abstracts | DGVS/DGAV
Kurzvorträge
Molekulare Therapie des kolorektalen Karzinoms Donnerstag, 18. September 2025, 10:50 – 12:07, Vortragsraum 11

Single cell characterization of resistance mechanisms to EGFR-targeted therapy in colorectal cancer patient derived organoids

Z Li
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
J G Gleixner
3   German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Heidelberg, Deutschland
,
R Riedke
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
3   German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Heidelberg, Deutschland
,
H Susak
4   German Cancer Research Center (DKFZ), Computational Genomics and Systems Genetics, Heidelberg, Deutschland
,
E Valentini
3   German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Heidelberg, Deutschland
,
T Mulholland
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
P Albrecht
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
J Yu
5   The First Affiliated Hospital of Sun Yat-sen University, Department of Andrology, Guangzhou, China
,
L Tondo
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
E Karabati
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
K Trikhirhisthit
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
P Sui
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
Y Petersen
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
,
T Miersch
3   German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Heidelberg, Deutschland
,
K Nowicki-Osuch
6   German Cancer Research Center (DKFZ), Junior Research Group Tumorigenesis and Molecular Cancer Prevention, Heidelberg, Deutschland
7   DKFZ Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Deutschland
,
O Stegle
4   German Cancer Research Center (DKFZ), Computational Genomics and Systems Genetics, Heidelberg, Deutschland
,
M P Ebert
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
7   DKFZ Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Deutschland
,
M Boutros
3   German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Heidelberg, Deutschland
,
J Betge
1   Heidelberg University, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Mannheim, Deutschland
2   German Cancer Research Center (DKFZ), Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, Heidelberg, Deutschland
7   DKFZ Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Deutschland
› Author Affiliations
› Further Information
Also available ateRef
 
 

    Introduction: EGFR-targeted therapy is a key component of RAS-wildtype colorectal cancer (CRC) treatment, yet efficacy varies significantly between patients. Understanding the differential molecular responses to EGFR blockade may lead to improved understanding of resistance and improving therapeutic outcomes.

    Objectives: To investigate the molecular response mechanisms of CRC patient-derived organoids (PDOs) on single-cell level, and to explore potential combination strategies to enhance treatment efficacy.

    Methodology: Whole-exome sequencing (WES) was performed to profile the mutational landscape of nine CRC-derived PDOs. Drug profiling assays assessed the sensitivity of these PDOs to multiple EGFR inhibitors. Single-cell RNA sequencing (scRNA-seq) was conducted on PDOs treated with an EGFR inhibitor or a vehicle control. Data were analyzed within individual patients to assess intra-tumoral heterogeneity, followed by integrated analysis across samples to investigate inter-tumoral differences, including those related to RAS status.

    Results: Drug screening confirmed that RAS wild-type PDOs exhibited greater sensitivity to EGFR inhibitors compared to RAS mutant PDOs. Single-cell RNA sequencing of nine integrated PDOs, with subset analysis of RAS wild-type samples, revealed that EGFR blockade led to widespread suppression of MAPK, EGFR, and PI3K pathway activities across tumor subpopulations, as inferred by PROGENy analysis. Further clustering identified a stem-like (undifferentiated) resistant subpopulation characterized by enhanced specific metabolic activity, and a proliferative progenitor-like resistant subpopulation associated with altered p53 pathway signaling. Trajectory and metabolic analyses indicated that EGFR inhibition promoted dedifferentiation of proliferative cells toward a stem-like state, accompanied by activation of metabolic pathways. Integrative transcriptional network analysis further nominated metabolism regulators and cell-cycle programs as potential therapeutic vulnerabilities to target distinct resistant subpopulations simultaneously.

    Conclusion: Our findings reveal potential adaptive resistance mechanisms in RAS wild-type CRC PDOs following EGFR inhibition, involving metabolic reprogramming and proliferative persistence.


     

    Publication History

    Article published online:
    04 September 2025

    © 2025. Thieme. All rights reserved.

    Georg Thieme Verlag KG
    Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany