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 4th 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 KRAS7,8 which represent the overwhelming majority of mutations seen in both TCGA9 and MSK10 CRC datasets available on cBioPortal11,12,13.

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 HDM218,19,20,21 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.

AKT1

AXIN2

CCND1

MAP2K1

PIK3CA

RAF1

AKT2

BAD

CTNNB1

MAPK8

PIK3CB

SMAD4

AKT3

BAX

FOS

MAPK9

PIK3CD

TCF7L2

APC

BCL2

GSK3B

MLH1

PIK3R1

TGFB1

APPL1

BRAF

JUN

MSH2

PIK3R2

TGFBR1

ARAF

CASP3

KRAS

MSH3

PIK3R3

TGFBR2

AXIN1

CASP9

LEF1

MSH6

RAC1

TP53

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

BRAF

JAK2

PTEN

EFGFR

KRAS

RAC1

GNAS

NRAS

TP53

HRAS

PIK3CA

RKO

BRAF FANCC MAP2K2
BRAF – His Tag FANCG MRE11A – His Tag

DICER1

GLUT1 TP53
EGFR MAP2K1

VACO 432

MAP2K1

MAP2K2

PIK3CA

LIM1215

KRAS

PIK3CA

DLD-1

AKT1

CHD2 – His Tag

MTAP

AKT1 + AKT2

CHECK1 + TP53

PIK3CA

AKT2

DICER1

PTPN14 – His Tag

ATG7

FBXW7

STAT3

ATR + TP53

GLUT1

TP53

BRAF

KRAS

ULK1

BRCA2

MAP2K1

USP7

CDKN1A

MAP2K2

XIAP

HCT116

ABL1

BRAF

FGFR3

MAP2K1

SMAD4

AKT1

CDK2

FLT3

MAP2K2

TRIM37 – His Tag

AKT2

CHEK1 + TP53

GNAS

MCTS1

TP53

AKT1 + AKT2

CHEK2 + TP53

HSPA8

MLH1

USP7

APC – His Tag

DIABLO

IDH1

MTAP

XIAP

APOC1

DICER1

IDH1 – His Tag

MTOR

ZBTB33

ARIDA1A

DNMT1

IDH2

NFE2L2

ZBTB33 – His Tag

ASF1A – His Tag

DNMT1 + DNMT3B

JAK2

PDGFRA

ZCCHC4 – His Tag

BAX

DNMT1 + DNMT3B + CDKN2A

KDM1A

PDPK1

BAZ2A – His Tag

DNMT3B

KDM5A

PIK3CA

BBC3

DOT1L – His Tag

KDM5C

PPARD

BBC3 + CDKN1A

E2F1 – His Tag

KIT

PTEN

BLM

EZH2 – His Tag

KRAS

PTTG1

BMI1 – His Tag

FBXW7

LIG3 – Floxed

SFN

Jenny Ashforth
Written by Jenny Ashforth, PhD, Senior Scientist in Cell Line Engineering
Jenny is a Senior Scientist for the cell line engineering group, working on the design and generation of custom cell lines for clients in biomedical research and drug discovery. Prior to joining Revvity in 2023, she conducted research for a large pharmaceutical company, focusing on the generation of cell lines that reflect cancer patient genetics and subsequent compound combination screening.

References

  1. Cancer Research UK. What is bowel cancer? [Online] November 30, 2021. [Cited: January 05, 2024.] https://www.cancerresearchuk.org/about-cancer/bowel-cancer/about-bowel-cancer.
  2. Cancer incidence for common cancers. [Online] 03 05, 2020. [Cited: 01 09, 2024.] https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared.
  3. World Health Organisation. Cancer Today. Global Cancer Observatory. [Online] International Agency for Research on Cancer. [Cited: 01 09, 2024.] https://gco.iarc.fr/today/online-analysis-pie
  4. Cancer Research UK. Risks and causes of bowel cancer. [Online] December 03, 2021. [Cited: January 05, 2024.] https://about-cancer.cancerresearchuk.org/about-cancer/bowel-cancer/risks-causes
  5. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. Aune D, Chan D S M, Lau R, Vieira R, Greenwood D C, Kampman E et al. 343, s.l. : BMJ, 2011. d6617.
  6. Red and processed meat intake and risk of colorectal adenomas: a systematic review and meta-analysis of epidemiological studies. Aune D, Chan DS, Vieira AR, Navarro Rosenblatt DA, Vieira R, Greenwood DC, Kampman E, Norat T. 611-27, s.l. : Cancer Causes Control., 2013, Vol. 4. PMID: 23380943.
  7. Colorectal cancer: molecular mutations and polymorphisms. Sameer, Aga Syed. 114, s.l. : Frontiers in oncology, 2013, Vol. 3.
  8. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Michel, M., et al. 2296, s.l. : Cancers, 2021, Vol. 13.
  9. Comprehensive molecular characterization of human colon and rectal cancer. Cancer Genome Atlas Network. 330-337, s.l. : Nature, 2012, Vol. 487(7407).
  10. A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers. Birsoy O, Robson M, Offit K, Taylor B, Berger M, Solit D, Weiser M, Saltz LB, Aguilar JG, Schultz N, Diaz LA, Stadler ZK. 1683-1692, s.l. : J Natl Cancer Inst, 2021, Vol. 13(12).
  11. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cerami, Ethan et al. 401-4, s.l. : Cancer discovery, 2012, Vols. 2,5.
  12. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Gao, Jianjiong et al. pl1, s.l. : Science signaling, 2013, Vols. 6,269.
  13. Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal. de Bruijn, Ino et al. 3861-3867, s.l. : Cancer research, 2023, Vols. 83,23.
  14. Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer. Zhang, Lu, and Jerry W Shay. 8, s.l. : Journal of the National Cancer Institute, 2017, Vol. 109.
  15. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Zhao, H., Ming, T., Tang, S. et al. 144, s.l. : Mol Cancer, 2022, Vol. 21.
  16. The Role of p53 Signaling in Colorectal Cancer. Liebl, M.C. and Hofmann, T.G. 2125, s.l. : Cancers, 2021, Vol. 13.
  17. Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials. Nishikawa, Shigeto, and Tomoo Iwakuma. 429, s.l. : Cancers, 2023, Vol. 15(2).
  18. The MDM2-p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study. LoRusso, P., Yamamoto, N., Patel, M. R., Laurie, S. A., Bauer, T. M., Geng, J., Davenport, T., Teufel, M., Li, J., Lahmar, M., & Gounder, M. M. 1802-1813, s.l. : Cancer discovery, 2023, Vol. 13(8).
  19. Abstract LB003: BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules. Gollner, Andreas, et al. 8_Supplement, s.l. : Cancer Res, 2023, Vol. 83.
  20. 2Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study. Takahashi, Shunji et al. 2361-2370, s.l. : Cancer science, 2021, Vols. 112,6.
  21. Gounder, Mrinal M et al. “A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients With Advanced Liposarcoma, Solid Tumors, or Lymphomas. 1714-1724, s.l. : Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2023, Vols. 41,9.
  22. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Zhu, G., Pei, L., Xia, H. et al. 143, s.l. : Mol Cancer, 2021, Vol. 20.
  23. The current understanding on the impact of KRAS on colorectal cancer,. Mingjing Meng, Keying Zhong, Ting Jiang, Zhongqiu Liu, Hiu Yee Kwan, Tao Su,. 111717, s.l. : Biomedicine & Pharmacotherapy, 2021, Vol. 140.
  24. Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review. Santarpia M, Ciappina G, Spagnolo CC, et al. 346-368, s.l. : Transl Lung Cancer Res, 2023, Vol. 12(2).
  25. KRAS p.G12C Mutation in Metastatic Colorectal Cancer: Prognostic Implications and Advancements in Targeted Therapies. Ottaiano, A., et al. 3579, s.l. : Cancers, 2023, Vol. 15.