Abstract 2571: An integral genomic/expression analysis reveals a cooperative role of APC and TP53 mutations in identifying cetuximab-sensitive colorectal cancer

The epidermal growth factor receptor (EGFR) is a major therapeutic target in metastatic colorectal cancer (CRC). Mutations in KRAS/NRAS have been identified as the resistance mechanisms to anti-EGFR antibody therapy (cetuximab/pantiumab). However, genomic understanding of the sensitivity to the EGFR-targeted therapy is lacking. A pre-specified, 203-gene cetuximab sensitivity (CTX-S) expression signature score was first validated on two previously published datasets: (1) 77 CTX-treated CRC tumors (progression free survival (PFS)>7 days), and (2) 147 in vitro CTX-treated CRC cell lines. The CTX-S signature was found to be consistently correlated with a newly developed 24-gene APC (truncating) mutations-specific Wnt/β-catenin score on four independent CRC datasets that also include Moffitt (n=468) and TCGA (n=624) CRC datasets. This promoted us to carry out a variety of analyses that revealed a cooperative role of mutant APC + mutant TP53 in identifying cetuximab sensitive subpopulations, which was further evidenced by additional validation analysis on two CRC PDX datasets (n=52 and n=98). While debating or inconclusive, other potential predictive markers of EGFRi therapies have been reported, including BRAF(V600E), PIK3CA mutations, loss of PTEN, and overexpression of HER2 as negative indicators, as well as increased EGFR copy number, and overexpression of EGFR ligands epiregulin and amphiregulin as positive indicators. Here, for the first time, we report that the mutant genes may cooperatively act as positive indicators of EGFRi response. Our study suggests that addition of the routine sequencing of APC and TP53 to extended RAS testing may refine the patient selection strategy to improve cetuximab/pantiumab response and potentially expand the therapeutic opportunity to previously-excluded mutant KRAS/NRAS patients who have “APC + TP53” mutations. Citation Format: Mingli Yang, Michael J. Schell, Andrey Loboda, Michael V. Nebozhyn, Jiannong Li, Jamie K. Teer, W. Jack Pledger, Timothy J. Yeatman. An integral genomic/expression analysis reveals a cooperative role of APC and TP53 mutations in identifying cetuximab-sensitive colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2571.