Epidermal Growth Factor Receptor and Colorectal Cancer

A crucial aspect of colorectal cancer development and progression is the regulation of the epidermal growth factor receptor (EGFR) pathway. This signaling pathway is one that has great significance in regulating cellular growth, survival, proliferation and differentiation. Dysregulation of the EGFR pathway is pivotal in tumorigenesis, making it an important target in cancer treatment.

In this article, we take a closer look at how the EGFR signaling pathway functions in normal cells, and how colorectal cancer develops as a result of its dysregulation.

EGFR, sometimes called ErbB-1 or HER1, is a transmembrane protein that is found on the surface of many different types of cells in the body, including the epithelial cells that line the gastrointestinal tract. It belongs to the epidermal growth factor receptor (EGF) family of receptor tyrosine kinases, which are high-affinity cell surface receptors that can bind to many polypeptide growth factor, cytokine and hormone ligands.

When a ligand binds to the extracellular portion of the EGFR, the receptor undergoes dimerization, in which two ligand-bound receptors join together to form a single unit. The dimerization process activates the intracellular tyrosine kinases through phosphorylation, and further activates other downstream cell signaling pathways.

The ligand binding triggers a series of biochemical reactions that activate several downstream signaling proteins, including Ras, Raf, and mitogen-activated protein kinase (MAPK). These proteins, in turn, activate a variety of other signaling pathways that are involved in cell growth, proliferation, differentiation and survival. The pathways activated by the ligand binding to EGFR are numerous and complex, as illustrated in the diagram below.

In normal cells, the EGFR pathway is tightly regulated and controlled to ensure that cell growth and proliferation occur only when necessary. However, in many types of cancers, including colorectal cancer, the EGFR pathway becomes dysregulated, leading to uncontrolled cell growth and proliferation.

There are several mechanisms by which dysregulation of the EGFR pathway can lead to the formation of colorectal tumors.

One mechanism through which carcinogenesis is possible involves overexpression of the EGFR receptor itself. However, compared to other cancers, oncogenic overexpression of EGFR is rare in colorectal cancer.

Colorectal cancer is more likely to arise when mutations are present in the KRAS gene, which is a component of the downstream Ras/MAPK pathway.

Mutations in the RAS genes can activate the Ras proteins, which then activate the downstream signaling pathways involved in cell growth and proliferation, even in the absence of ligand binding to the EGFR receptor. In fact, mutations or alterations in other components of the pathway, including the downstream signaling proteins Raf, MEK, and MAPK can dysregulate the EGFR pathway and lead to tumorigenesis.

Overall, dysregulation of the EGFR pathway is a key driver of colorectal tumor formation, and targeting this pathway has become a major focus of cancer research and drug development. Several drugs that target the EGFR pathway, including cetuximab and panitumumab, have been developed and are currently used in the treatment of colorectal cancer. However, the development of resistance to these drugs remains a major challenge, and further research is needed to fully understand the complex interactions between the EGFR pathway and other signaling pathways involved in colorectal tumor formation and progression.

While it was originally believed that the mutated Ras protein drives cancerous growth separately from wild-type Ras, this has since been proven otherwise. Put simply, wild-type Ras “cooperates” with mutant Ras to promote oncogenesis by regulating downstream effector signaling, resulting in therapeutic resistance in Ras-mutated cancers.

Understanding the ways in which EGFR dysregulation can lead to cancerous growth is key in identifying the appropriate treatment for different patients. Patients with mutations in the Ras gene generally would not respond well to treatments that target the EGFR receptor directly, as the Ras protein is able to activate the downstream signaling pathways even in the absence of a ligand binding to the receptor.

Nonetheless, for patients with wild-type Ras, there are at least two drugs that have been formulated to directly target EGFR as part of colorectal cancer treatment regimens. Cetuximab and panitumumab are monoclonal antibodies that bind to the EGFR on tumor cells to block the signal transduction pathway and inhibit cellular growth and proliferation.