ERBB2 deficiency enhances colorectal cancer progression through EGFR-dependent compensatory mechanisms

Abstract ERBB2 is mutated or amplified in a subset of colorectal cancers (CRCs) and may be a marker of resistance to anti-epidermal growth factor receptor (EGFR) therapeutics and help to identify patients who may benefit from ERBB2-directed therapeutic management. To further investigate the role of ERBB2, we generated a population of Erbb2 -deficient Apc Min/+ mice ( Apc Min/+ , Erbb2 f/f , Tg(Vil-Cre) ). We found that Erbb2- deficieny modulates CRC initiation but enhances progression in the Apc Min/+ model. Transcriptomic analysis predicted EGFR activation, which likely mediates the progression that leads to the larger tumors observed in the absence of functional ERBB2. Further in silico predictions confirmed this prediction and indicated involvement of oncogenic Kras mutations, which are essential in determining the progression program by which this operates, similarly to EGFR-independent CRC. Further analysis confirmed activation of EGFR and subsequent activation of MAPK pathway through MEK/ERK. These preclinical analyses suggest an important role for ERBB2 in CRC and highlight the need for further characterization to identify and predict the merit of potential combinatory therapies and patient populations that may benefit from ERBB2-directed therapy in tandem with EGFR therapy.