Repurposing EGFR Inhibitor Utility in Colorectal Cancer in Mutant APC and TP53 Subpopulations

Abstract

Background: EGFR is a major therapeutic target for colorectal cancer. Currently, extended RAS/RAF testing identifies only nonresponders to EGFR inhibitors (EGFRi). We aimed to develop a mutation signature that further refines drug-sensitive subpopulations to improve EGFRi outcomes. Methods: A prespecified, 203-gene expression signature score measuring cetuximab sensitivity (CTX-S) was validated with two independent clinical trial datasets of cetuximabtreated patients with colorectal cancer (n ¼ 44 and n ¼ 80) as well as an in vitro dataset of 147 cell lines. The CTX-S score was then used to decipher mutated genes that predict EGFRi sensitivity. The predictive value of the identified mutation signature was further validated by additional independent datasets. Results: Here, we report the discovery of a 2-gene (APCþTP53) mutation signature that was useful in identifying EGFRi-sensitive colorectal cancer subpopulations. Mutant APCþTP53 tumors were more predominant in left-versus right-sided colorectal cancers (52% vs. 21%, P ¼ 0.0004), in microsatellite stable (MSS) versus microsatellite instable (MSI) cases (47% vs. 2%, P < 0.0001), and in the consensus molecular subtype 2 versus others (75% vs. 37%, P < 0.0001). Moreover, mutant APCþTP53 tumors had favorable outcomes in two cetuximab-treated patient-derived tumor xenograft (PDX) datasets (P ¼ 0.0277, n ¼ 52; P ¼ 0.0008, n ¼ 98). Conclusions: Our findings suggest that the APC and TP53 combination mutation may account for the laterality of EGFRi sensitivity and provide a rationale for refining treated populations. The results also suggest addition of APCþTP53 sequencing to extended RAS/RAF testing that may directly increase the response rates of EGFRi therapy in selected patients. Impact: These findings, if further validated through clinical trials, could also expand the utility of EGFRi therapies that are currently underutilized.

The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

“…This is further supported by in vitro studies showing a higher Cetuximab sensitivity in cells with down-regulated p53 [ 92 ]. Patients with mCRC harboring mutations in both APC and TP53 showed the highest sensitivity to treatment with Cetuximab, and were associated with an overall favorable outcome [ 93 ]. Those patients with tumors harboring wt- KRAS and a p53 mutation treated with Cetuximab-based chemotherapy had a longer time to progression (TTP) than those without p53 mutation [ 94 ].…”

Wild-typeAPCIs Associated with Poor Survival in Metastatic Microsatellite Stable Colorectal Cancer

“…Colorectal cancers with mutated APC conferred better overall survival (OS) than wild‐type tumors when treated with an epidermal growth factor receptor (EGFR) inhibitor [11]. These data suggest that APC mutation may account for EGFR inhibitor sensitivity and provide rationale for refining treatment guidelines in addition to extended RAS/RAF testing [11, 12].…”

Qualitative Ras pathway signature for cetuximab therapy reveals resistant mechanism in colorectal cancer

“…5). These comutations of APC and TP53 genes have been reported to be associated with sensitivity to cetuximab therapy in Ras‐normal mCRC patients [25].…”