Abstract
Simple SummaryColorectal 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.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.
Highlights
Epidermal Growth Factor Receptor (EGFR) inhibitors are effective in the subset of RAS (KRAS, NRAS) wild-type colorectal cancer (CRC) patients
TP53 mutations were most common in CMS2 but least common in CMS3 subtype
When RAS (KRAS/NRAS)-mutated CRC tumors were associated with combined AP mutations (i.e., APK mutations), the cetuximab sensitivity (CTX-S) scores were significantly higher. This was seen in the CMS2 class, and in the other consensus molecular subtyping (CMS) cohorts (Figure S2B). These results suggest that combined AP mutations can select a subset of patients within each CMS cohort that may benefit most from EGFR inhibitor therapy, thereby expanding the utility of this drug class
Summary
Epidermal Growth Factor Receptor (EGFR) inhibitors are effective in the subset of RAS (KRAS, NRAS) wild-type colorectal cancer (CRC) patients. A few studies have reported a conflicting, but possibly predictive role, of consensus molecular subtype (CMS) classification for the selection of patients for EGFRi therapy [8,9]. The classification categorizes CRC into one of four consensus molecular subtypes with distinguishing features: CMS1 (immune), hypermutated, microsatellite unstable tumors with strong immune activation; CMS2 (canonical), epithelial, with marked WNT and MYC signaling activation; CMS3 (metabolic), epithelial and with evident metabolic dysregulation; CMS4 (mesenchymal), characterized by transforming growth factor–β activation, stromal invasion and angiogenesis, a fair number remain unclassified. The prevalence of CMS classes varies by tumor sidedness and stage of the tumors with CMS1 and CMS3 subtypes enriched in right-sided tumors and early-stage CRC, while CMS2 enrichment was noted in left-sided tumors and CMS4 class most common in advanced tumors [10,11,12,13,14]
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