The importance of ERBB receptor tyrosine kinase signaling in colorectal cancer---Implications for EGFR-targeted therapies.

摘要

Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the United States. Our current understanding of the molecular pathways associated with this malignancy has led to the development of novel molecule targeted therapies, exemplified by small molecule inhibitors and monoclonal antibodies targeting the epidermal growth factor receptor (EGFR/ERBB1). EGFR is a member of the ERBB family of receptor tyrosine kinases consisting of EGFR(ERBB1), ERBB2, ERBB3 and ERBB4. They are transmembrane receptors to elicit cellular signaling pathways in response to extracellular stimuli. Upon ligand binding, ERBB family receptors dimerize to phosphorylate the cytoplasmic kinase domain, resulting in activation of complex downstream signaling cascades, among which the RAS/MEK/MAPK pathway delivers pro-proliferative signals and the PI3K/ATK/mTOR cascade act as a pro-survival pathway. The ERBB family members play a pivotal role in many aspects of cellular biology. As such, misregulation or dysfunction of ERBB receptors has been implicated in many disease states, in particular cancers of epithelial tissues, making the ERBB pathways valuable targets for pharmacological inhibition in cancer treatment. For EGFR-targeted therapies, although preclinical and early clinical studies presented encouraging results, the large-scale clinical trials clearly demonstrate that the majority of patients do not respond. This discrepancy demonstrates that little is known about the mechanisms underlying tumor response to EGFR-targeted therapies. In this study, by using ApcMin mouse models of familial CRC, we generated mice with Egfr deletion exclusively in the intestinal epithelium and demonstrated that although EGFR signaling is critical for establishment of most intestinal tumor, tumors can arise independent of EGFR activity. Moreover, we identified gene expression signatures of EGFR-independent tumors and provided evidence for ERBB3 activity in mediating compensatory pathways. Consequently, we further established the importance of ERBB3 pathway during intestinal tumorigenesis with both ApcMin mouse models of familial CRC and azoxymethane (AOM) model of sporadic CRC. Finally, by utilizing mice harboring a hypomorphic Egfr allele on four different strain backgrounds, we demonstrated the strong background modulation of tumor response to EGFR inhibition. These studies may advance understanding of ERBB biology during intestinal tumorigenesis and help design better therapies in combination with EGFR-targeted agents.