Colorectal cancer: making a global challenge patient-centric

Colorectal cancer (CRC) is the abnormal cell growth starting in the lining of the large intestine or rectum¹. In the UK CRC is the 4^th most common type of cancer diagnosed every year² and third most common globally³.

Interestingly CRC is linked to both avoidable and unavoidable risk factors, for example age is an unavoidable risk factor for most cancers including CRC⁴, where more than 40% of cases occur in patients over the age of 75. Diet is considered an avoidable risk factor for CRC, for instance a low fiber diet has been linked to 30% of colorectal cancer cases⁴, and a high fiber diet has been shown to reduce the risk of colorectal cancer⁵. Another dietary risk factor is the consumption of red or processed meats⁶ which has been linked to an increase in CRC. As the risk of cancer increases with age it is important to control avoidable risk factors including smoking, obesity and alcohol consumption⁴.

The diagnosis of colorectal cancer involves a colonoscopy and biopsy of the suspected cancerous tissue. The typical pathological indicators in the biopsy will include abnormal physiological structure and lack of the expected layering in the bowel. This will give an indication of the stage and grade of the cancer. In addition to tissue physiology, genetic testing on the cancerous cells is a useful tool to indicate which mutations are present, providing critical knowledge for the use of targeted therapeutics for common mutations.

There are certain populations of colorectal cancer patients which share similar mutations, including point mutations resulting in altered protein production or loss of function mutations causing a truncated protein. Once a population is identified it is important to develop targeted treatments which will overall improve patient outcomes. Although there are many mutations seen in CRC, key mutations associated with CRC include APC, TP53 and KRAS^7,8 which represent the overwhelming majority of mutations seen in both TCGA⁹ and MSK¹⁰ CRC datasets available on cBioPortal^11,12,13.

Mutations in APC are often seen in CRC, with somatic mutations found in over 80% of CRC cases¹⁴. As a tumor suppressor, APC is important for cell cycle regulation. Mutations in APC cause Wnt signalling activation, a driving factor in CRC development and progression¹⁵. Although there are currently no targeted therapies for patients with mutated APC, it is a known risk factor and often a key indicator of CRC diagnosis.

Many cancers have mutations in the TP53 gene, including CRC. The protein p53 is a transcription factor with tumor suppressor functionality, closely regulating cell cycle and DNA damage response¹⁶. When dysregulated in cancer, we see a rapid proliferation of cells and metastasis. Typically, patients with TP53 mutations are more resistant to chemotherapy⁸ but have provided a well characterized target for therapeutic development¹⁷. There are many FDA approved drugs which have been shown to have additional functionality against mutant p53¹⁷ even though these were not the initial intended target. There are promising results from clinical trials which target HDM2^18,19,20,21 a negative regulator of p53 signalling pathway, allowing p53 activation and subsequent tumor growth inhibition.

Around 40% of CRC cases have a mutation in KRAS²², a prominent oncogene, often resulting in uncontrolled cell proliferation and angiogenesis. Patients with mutations in KRAS often have a worse overall outcome but these mutations can be used as a predictive marker for targeted treatments²³. There are many strategies under investigation for targeting KRAS mutant CRC, both direct inhibition of KRAS and indirect targeting of proteins up and downstream in the KRAS pathway²³. Although many of the trials and approval for KRAS targeted therapies are focused on lung cancer²⁴, it is easy to see the potential for these drugs in CRC²⁵.

For the development of specific targeted therapies, the standard process of drug development relies heavily on cell line models with different genetic backgrounds, specific to the intended therapeutic target. it is necessary to develop drug in a genetic landscape that reflects the intended patient population to increase the chances of downstream success. There is a growing trend in the pharmaceutical industry of assessing the efficacy of existing therapies in different patient populations, often represented by cell line models. not only does this reduce the timelines for drugs to become available, but it also creates a more cost-effective drug discovery pipeline by utilizing high throughput screening to identify patient populations beyond the initial intended target who could benefit from the drug. The development and repurposing of targeted therapies is a step towards improving patient outcomes in CRC.

Here at Revvity Cambridge, we have a large collection of cell models across haploid and cancer lines. Using Kegg Pathway Assessment, we compared known genes implicated in colorectal cancer with our catalogue of HAP1 and Cancer cell lines. Of the 62 colorectal cancer genes identified in the Kegg Assessment, we have 42 cell lines available. Check out the list below for gene coverage and links to product pages.

Gene knockouts available in HAP1 and Cancer Cell Lines
Gene knockouts available in Cancer Cell Lines

Additionally, Horizon carries several cancer-related mutations and tagged proteins in known relevant colorectal cell lines including SW48, RKO, VACO 432, LIM1215, DLD-1, and HCT116. Browse the tables below for your cell line or gene of interest and links to product pages.

SW48 RKO

RKO

VACO 432

LIM1215

DLD-1

HCT116

References

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