ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epidermal growth factor receptor (EGFR)-targeted therapy is crucial for RAS wildtype metastatic colorectal cancer (CRC).
• Predictive markers for EGFR-targeted therapy resistance in CRC are limited, hindering optimal patient stratification.
• Existing markers like RAS wildtype status do not fully predict treatment response.

Purpose of the Study:

• To identify novel predictive markers for EGFR-targeted therapy response in metastatic colorectal cancer.
• To correlate molecular profiles (NGS mutations, EGFR methylation/expression, E-cadherin) with Cetuximab response in CRC cell lines and patient samples.

Main Methods:

• Investigated response of 7 CRC cell lines to Cetuximab.
• Analyzed NGS-based mutation profiles, EGFR promoter methylation, EGFR expression, and E-cadherin expression.
• Examined molecular markers in tumor specimens from 25 CRC patients treated with EGFR inhibitors.

Main Results:

• EGFR promoter methylation, EGFR expression, MSI, and CIMP status did not predict treatment response.
• EGFR-targeted therapy response was observed in RAS exon 2 p.G13 mutated CRC and linked to PIK3CA exon 9 mutations.
• Non-response was associated with ATM mutations and low E-cadherin expression; E-cadherin knockdown abrogated Cetuximab response in responsive cells.

Conclusions:

• ATM mutations and low E-cadherin expression are potential novel supportive predictive markers for EGFR-targeted therapy in CRC.
• These markers may improve patient stratification beyond current RAS wildtype status.
• Further validation is needed for clinical application in colorectal cancer treatment decisions.