APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes

SIMPLE SUMMARY: Colorectal cancer (CRC) is a major cause of cancer deaths. Cetuximab is an FDA-approved, underutilized therapeutic targeting the epidermal growth factor receptor (EGFR) in metastatic CRC. To date, despite selection of patients with wild-type RAS, it is still difficult to identify patients who may benefit from EGFR inhibitor (e.g., cetuximab) therapy. Our aim is to molecularly classify CRC patients to better identify subpopulations sensitive to EGFR targeted therapy. APC and TP53 are two major tumor suppressor genes in CRC whose mutations contribute to tumor initiation and progression and may identify cetuximab-sensitive tumors. Recently, it has been suggested that the consensus molecular subtype (CMS) classification may be used to help identify cetuximab-sensitive patients. Here, we report an analysis of multiple CRC tumor/PDX/cell line datasets using combined APC and TP53 mutations to refine the CMS classification to better predict responses to cetuximab to improve patient outcomes. ABSTRACT: Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across all CMS classes. Similar results were also obtained in independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.