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Updated: Oct 28, 2025
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer
Deepak Vangala1,2, Swetlana Ladigan1,2, Sven T Liffers3,4
1Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780, Bochum, Germany.
Background:
The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms.
Methods:
We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.
Results:
In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies.
Conclusions:
Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.
Insights
Secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is often driven by transcriptional reprogramming, not just gene mutations. Patient-derived xenograft models reveal novel SR pathways, enabling targeted therapy development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Secondary resistance (SR) to anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (mCRC) presents a significant clinical challenge.
- The precise molecular mechanisms underlying SR development remain incompletely understood, hindering the design of effective treatment strategies.
Purpose of the Study:
- To investigate the molecular mechanisms of anti-EGFR SR in mCRC using patient-derived xenograft (PDX) models.
- To dissect the molecular basis of SR through in vivo selection and multi-omics analysis.
- To identify novel therapeutic targets for overcoming anti-EGFR resistance.
Main Methods:
- Analysis of 21 wildtype CRC PDX models for anti-EGFR sensitivity.
- Generation of 31 anti-EGFR SR tumors through chronic in vivo cetuximab treatment.
- Multi-omics profiling (genomics, transcriptomics) and gene set enrichment analysis to identify SR pathways.
- Validation of identified SR pathways through targeted therapy in SR PDX models.
Main Results:
- Efficient establishment of in vivo anti-EGFR SR in CRC PDX models.
- Demonstration of parallel evolution of SR with independent molecular mechanisms, with gene mutations explaining SR in only a subset of models.
- Identification of transcriptional reprogramming as a common SR mechanism, frequently activating RAS signaling.
- Discovery of novel SR mechanisms including cAMP and STAT3 signaling activation, and growth factor-mediated paracrine/autocrine signaling.
- Successful targeted therapy of SR xenografts by addressing identified transcriptional changes.
Conclusions:
- SR PDX models offer a valuable platform for studying SR mechanisms and testing novel therapeutic strategies in a preclinical setting.
- Transcriptional reprogramming is a prevalent mechanism driving anti-EGFR SR in CRC, potentially more common than previously recognized.
- Multi-omics analysis of SR tumor tissues is crucial for a comprehensive understanding of anti-EGFR resistance in CRC, guiding the development of more effective treatments.
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