Erlotinib Suppresses Tumorigenesis in a Mouse Model of Colitis-Associated Cancer

Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms remain unclear. No definitive preventative agent against CAC is currently established in the clinical setting. We investigated the molecular mechanisms of CAC in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and assessed the antitumor efficacy of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR). Erlotinib premixed with AIN-93G diet at 70 or 140 parts per million (ppm) inhibited tumor multiplicity significantly by 96%, with ~60% of the treated mice exhibiting zero polyps at 12 weeks. Bulk RNA-sequencing revealed more than a thousand significant gene alterations in the colons of AOM/DSS-treated mice, with KEGG enrichment analysis highlighting 46 signaling pathways in CAC development. Erlotinib altered several signaling pathways and rescued 40 key genes dysregulated in CAC, including those involved in the Hippo and Wnt signaling. These findings suggest that the clinically-used antitumor agent erlotinib might be repurposed for suppression of CAC, and that further studies are warranted on the crosstalk between dysregulated Wnt and EGFR signaling in the corresponding patient population. To investigate the genetic, epigenetic, and signaling pathway mechanisms by which CAC manifests and is therapeutically affected by erlotinib, differential gene expression profile analysis was performed using RNA sequencing of total RNAs isolated from the colons of C57BL/6J mice. The comparative groups consisted of (1) vehicle control, (2) CAC, and (3) CAC+Erlotinib treatment. Gene ontology and KEGG pathway enrichment was performed on the gene lists.