Implications of ERBB Receptor Tyrosine Kinase Signaling in Resistance to EGRF-Targeted Therapies in Colorectal Cancer

Colorectal cancer (CRC) ranks among the third most common human malignant diseases and is one of the leading causes of cancer-related deaths globally. The epidermal growth factor receptor (EGFR) is recognized as an important player in CRC initiation and progression. EGFR is a transmembrane receptor tyrosine kinase that is commonly upregulated in many human epithelial cancers including CRC (Roskoski 2014). The activation of these receptor is tightly regulated via ligand binding leading to downstream signaling that influence biological process like cell proliferation, apoptosis, angiogenesis, cell adhesion, mobility, invasion and metastasis. EGFR-targeted therapies have been approved for CRC treatment. However, increasing evidence suggests that only 15% of CRC patients initially respond to these therapies due to high levels of primary resistance, and those who show initial response eventually become refractory to treatment and relapse under the treatment (secondary resistance). Efficacy of anti-EGFR therapy in humans is proven to be influenced by the mutational context of the cancer. In this dissertation we review the mechanisms of resistance to anti-EGFR therapies and the critical roles of ERBB members in CRC, with an emphasis on different approaches to overcome this resistance and potential future directions for more tailored cancer therapies. In chapter 2, we demonstrated that colorectal tumors can initiate through an EGFR-independent mechanism, characterized by activation of IL10 and ERBB4 signaling, with an accelerated growth rate mediated by a state of anergy. The existence of this EGFR-independent mechanism of CRC progression could explain the lack of response in a subset of CRC, and suggests that targeting EGFR would be most effective for those cancers that are dependent upon EGFR signaling. Additionally, in chapter 3, we also demonstrate the importance of ERBB3-mediated intestinal tumorigenesis through activation of PI3K/AKT signaling pathway activation, providing a valuable target for therapeutic intervention. The differential expression of ERBB family and the high resistance to anti-EGFR treatment in CRC patients suggest that therapies targeting more than signaling pathway might be the most effective treatment in the future. The studies done in this dissertation advances our understanding of ERBB family biology during colonic tumorigenesis, ultimately contributing to better therapies for CRC