Genomic alterations in the WNT/β-catenin pathway and resistance of colorectal cancer cells to pathway-targeting therapies.

Abstract

Aim: Colorectal cancer is the most prevalent gastrointestinal malignancy with limited therapeutic options in the metastatic setting. The WNT/β-catenin/adenomatous polyposis coli (APC) pathway is commonly deregulated in the disease and presents a rational target for therapeutic exploitation.

Methods: The publicly available genomic data from the colorectal cancer cohort of the Cancer Genome Atlas (TCGA) were used to define groups of colorectal cancers with alterations in APC or other key genes of the WNT/β-catenin/APC pathway and to identify genomic characteristics of interest in each group. In vitro sensitivity data for drugs targeting the pathway were compiled from the Genomics of Drug Sensitivity in Cancer (GDSC) project.

Results: Three-fourths of colorectal cancers possessed APC alterations and about one in four of these cases possessed also concomitant alterations in other genes of the WNT/β-catenin/APC pathway, including RNF43, CTNNB1, and TCF7L2. Colorectal cancers with alterations in one or more of the three genes of the WNT/β-catenin pathway, RNF43, CTNNB1, and TCF7L2, in the absence of APC alterations, were frequently microsatellite instability (MSI) high and had high tumor mutation burden (TMB). Cancers with these same alterations in the three genes with or without APC alterations presented a high frequency of mutations in receptor tyrosine kinases, PI3K/AKT pathway genes, and DNA damage response genes. Cell lines without mutations in WNT/β-catenin/APC pathway components displayed numerically greater sensitivity to inhibitors of the pathway in vitro.

Conclusions: Groups of colorectal cancers differing in WNT/β-catenin/APC pathway alterations present diverse genomic landscapes that could have therapeutic implications for the rational development of inhibitors of the pathway.