Investigating the role of ERBB2 during colorectal cancer in the ApcMin/+ mouse model

The ERBB family consists of four receptors (EGFR, ERBB2, ERBB3, and ERBB4) that are critical in normal development and physiology of mammalian gastrointestinal epithelial tissues. Amplifications or mutations in ERBB2 are commonly found in CRC, suggesting a possible therapeutic target. Patients with ERBB2-amplification in breast and gastroesophageal cancer are routinely treated with the ERBB2-directed antibody trastuzumab. However, ERBB2 is not commonly targeted in clinical practice of treating CRC. Notably, ERBB2 status could guide therapy as a negative marker for EGFR-targeted therapy (cetuximab) and identify likely responders for ERBB2-directed therapy. Although the most common marker for negative efficacy of anti-EGFR therapy is KRAS mutations, many patients with KRAS wild-type tumors do not respond to EGFR inhibition. As the primary EGFR-directed antibodies for CRC do not inhibit ERBB2, alterations increasing ERBB2 may serve as a superior negative predictor of EGFR therapy since previous studies demonstrate that ERBB2 amplification confers resistance to cetuximab in preclinical models. Despite the compelling evidence, the utility of ERBB2 as a target for molecular therapy of primary CRC tumors in preclinical models is largely unexplored. As such, our goal is to further characterize the influece of ERBB2 in the initiation and progression of CRC.