APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Consensus Molecular Subtyping (CMS) is used in colorectal cancer (CRC) research.
• EGFR inhibitors like cetuximab are key therapies for some CRC patients.
• Predicting response to cetuximab remains a challenge.

Purpose of the Study:

• To investigate if mutations in tumor suppressor genes APC and TP53 (AP) can refine CMS for predicting cetuximab response.
• To evaluate AP mutations as biomarkers for cetuximab sensitivity in CRC.

Main Methods:

• Classified 433 CRC tumors into CMS1-4 subtypes.
• Assessed cetuximab sensitivity (CTX-S) scores in tumors with and without AP mutations across CMS classes.
• Validated findings in TCGA and PDMR collections and in vitro cell lines.

Main Results:

• Combined AP mutations were enriched in CMS2 and CMS4 subtypes.
• AP-mutated CRCs showed significantly higher CTX-S scores across all CMS classes.
• In vitro studies confirmed cetuximab sensitivity in CMS2 cell lines with AP genotypes.

Conclusions:

• The APC/TP53 mutation signature refines CMS classification for CRC.
• AP mutations serve as a convenient biomarker to identify CRC subpopulations sensitive to EGFR inhibitors.