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A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer
Serena Bonin1, Marisa Donada1, Gianni Bussolati2
1Department of Medical Sciences, University of Trieste, Cattinara Hospital-Surgical Pathology Building, Strada di Fiume 447, 34149, Trieste, Italy.
Abstract:
Genetic factors are known to affect the efficiency of therapy with monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) in patients with metastatic colorectal cancer (mCRC). At present, the only accepted molecular marker predictive of the response to anti-EGFR mAbs is the somatic mutation of KRAS and NRAS as a marker of resistance to anti-EGFR. However, only a fraction of KRAS wild-type patients benefit from that treatment. In this study, we show that the EGFR gene polymorphism rs1050171 defines, independently of RAS mutational status, a sub-population of 11 % of patients with a better clinical outcome after anti-EGFR treatment. Median PFS for patients with the GG genotype was 10.17 months compared to 5.37 of those with AG + AA genotypes. Taken together, our findings could be used to better define CRC populations responding to anti-EGFR therapy. Further studies in larger independent cohorts are necessary to validate the present observation that a synonymous polymorphism in EGFR gene impacts on clinical responsiveness.
Insights
A new EGFR gene polymorphism (rs1050171) identifies a subset of metastatic colorectal cancer (mCRC) patients who benefit more from anti-EGFR monoclonal antibody (mAb) therapy, independent of RAS mutations.
Area of Science:
- Oncology
- Genetics
- Pharmacogenomics
Background:
- Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) are used for metastatic colorectal cancer (mCRC).
- RAS (KRAS/NRAS) mutational status is the primary molecular marker predicting response to anti-EGFR therapy, but many RAS wild-type patients do not benefit.
- There is a need for additional biomarkers to identify patients who will respond to anti-EGFR treatment.
Purpose of the Study:
- To investigate the impact of EGFR gene polymorphisms on the efficacy of anti-EGFR mAb therapy in mCRC patients.
- To identify novel genetic markers that predict response to anti-EGFR treatment beyond RAS mutational status.
Main Methods:
- Retrospective analysis of EGFR gene polymorphism rs1050171 in a cohort of mCRC patients treated with anti-EGFR mAbs.
- Correlation of EGFR genotype with progression-free survival (PFS).
- Analysis independent of RAS mutational status.
Main Results:
- The EGFR gene polymorphism rs1050171 identified an 11% sub-population of patients with improved clinical outcomes.
- Patients with the GG genotype had a median PFS of 10.17 months, compared to 5.37 months for those with AG + AA genotypes.
- This effect was observed independently of RAS mutational status.
Conclusions:
- The EGFR gene polymorphism rs1050171 is a potential predictive biomarker for anti-EGFR mAb therapy in mCRC.
- This finding could help refine patient selection for anti-EGFR treatment, improving therapeutic efficacy.
- Further validation in larger cohorts is required to confirm the impact of this synonymous EGFR polymorphism on clinical response.
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