Introduction

Colorectal cancer (CRC) is a type of cancer that affects the bowel and gut. Old age, diet, lifestyle, and history of adenomatous polyps are predictors of CRC; however, there is an increasing incidence of young people with the disease today.¹ The prevalence of CRC as the third most common cancer globally means that it is necessary to find new treatment methods. 

One of, how we can combat CRC is through targeted therapy. Unlike traditional treatment options like chemotherapy and radiation, it uses drugs or monoclonal antibodies to target specific molecules in cancer cells. It prevents them from growing rapidly and spreading to other body parts (metastasis).² It can be a more precise and focused way to treat cancer. This article will describe how targeted therapy can be used for colorectal cancer and provide insights into current and future research.

Mechanism of targeted therapy

Cancer and normal cells have molecular differences that distinguish them from one another. Scientists can take advantage of these markers to develop drugs for cancer.

In colorectal cancer, these manifest as genetic mutations that cause the cells to escape the normal cell cycle and keep growing. In around 80% of CRC cases, a mutant form of the tumour, suppressor gene APC (adenomatous polyposis coli), is present in the cells.³

Other target molecules that are used in the development of drugs to fight CRC include:

• Other components of signalling pathways involved in cell division
• Kras/Braf, also responsible for this process
• MSI (microsatellite instability, areas which are susceptible to mutations)
• P53, a gene that prevents cancer

Cell growth is a highly regulated process, depending on cell signalling pathways. Cells can respond to molecular signals given off by the cells around them, which can in turn set off a series of chemical events that can lead to growth, proliferation, and death (apoptosis).

Targeted therapy acts on protein molecules that are involved to interrupt or fix processes that have gone wrong. By tailoring treatments to a patient’s genetic profile, we can achieve personalised health outcomes through precision medicine.  

Key targets in colorectal cancer

Epidermal growth factor receptor (EGFR) inhibitors

This is a gene that is overexpressed in 60% to 80% of colorectal cancer cases and typically has poor outcomes. It makes a protein that helps tumours to survive, and it also dysregulates the cell cycle.⁴

Examples of monoclonal antibodies that target EGFR include:

• Cetuximab
• Panitumumab

They effectively treat metastatic CRC in patients with the normal version of the RAS gene.⁵

Vascular endothelial growth factor (VEGF) inhibitors

Vascular endothelial growth factor helps tumours to survive by providing them with an increased blood supply. Bevacizumab is another monoclonal antibody developed to inhibit the action of VEGF and has been shown to improve the survival of patients with CRC.⁶

BRAF mutations

When mutated, the BRAF V600E gene leads to uncontrolled cell division and growth, leading to tumour formation. These mutations can be targeted by the BRAF inhibitors such as vemurafenib and dabrafenib.⁷

Immunotherapy and microsatellite instability (MSI)

Patients with high microsatellite instability can benefit from immunotherapy, using checkpoint inhibitors. These target cancer cells to destroy them. Some examples of checkpoint inhibitor drugs include pembrolizumab and nivolumab.⁸

Types of targeted therapy drugs for CRC

Monoclonal antibodies are proteins that can target a specific molecule on the surface of cells (antigens). Epidermal growth factor and vascular endothelial growth factor inhibitors are monoclonal antibodies that bind to the regions of the molecules that lead to their activity. By blocking these sites, it can hinder tumour formation.

Small molecule inhibitors work against the action of specific structures, such as BRAF or MEK that are involved in signalling pathways that when unregulated growth cause tumours to form. By blocking these sites, it stops uncontrolled cell division.⁹

Immunotherapy agents such as checkpoint inhibitors treat mismatch repair deficient tumours. Our immune system uses checkpoint proteins to prevent immune responses from being too strong and killing our cells. Checkpoint inhibitors block these proteins from binding, allowing our immune system to deal with cancerous cells.¹⁰ CRC has been used to treat tumours deficient in mismatch repair proteins that regulate mutated DNA.

Selection criteria for targeted therapy

Healthcare providers can provide molecular profiling and genetic testing for mutations in:

• MSI
• KRAS
• NRAS
• BRAF

Alternatively, biomarker-driven treatment can guide therapy choices, as they can indicate how well a patient is likely to respond to different treatments. Biomarkers are proteins or molecules that can act as an identification tool. For example, KRAS and NRAS mutations reduce the effectiveness of EGFR inhibitors, so these would not be a suitable mode of therapy for a patient with this genetic profile.¹¹

Benefits of targeted therapy in CRC

The advantages of targeted therapy in CRC include:

• Increased specificity, due to direct action on cancer cells that spares healthy cells
• Well-tolerated by the body compared to traditional chemotherapy ¹²
• Improved outcomes for subgroups of patients with specific genetic mutations such as BRAF and MSI-high 
• Opportunity for combination therapy, working synergistically with chemotherapy and immunotherapy¹³

Challenges and limitations

Disadvantages of targeted therapy for CRC include:

• Drug resistance to targeted agents – KRAS can form resistance through mutations.
• Limited effectiveness in some subgroups, with a lack of response in patients with specific mutations such as KRAS to EGFR inhibitors¹⁴
• Costly for patients and healthcare providers

Current research and future directions

Next-generation sequencing and other diagnostic tools such as liquid biopsies, machine learning, and AI can also lead to the emergence of personalised medicine approaches tailored to the individual patient.¹⁵

Current research focuses on finding new targets in CRC, which will aid in developing new inhibitors and combination therapies based on the patient’s genetic makeup.¹⁶ One of these is a human epidermal growth factor receptor 2, also known as HER2, found in 5% of CRC cases.¹⁷

Summary

Targeted therapy has helped to improve the survival rates and quality of life for patients with subgroups of genetic mutations, allowing them to avoid side effects from non-specific modes of treatment. Current movements in CRC therapy involve using biomarkers, which can provide cues on how healthcare providers can proceed with treatments based on effectivity to the patient. Though the prospect of personalised therapy is exciting, ongoing research focuses on making healthcare accessible to patients who need it and improving in areas where drugs elicit no positive response.