Ali Eldough

Colon cancer currently ranks as the second and third most frequent cancer in males and females, respectively, and it ranks fourth and third for cancer-related deaths in males and females, respectively^1,2. The lifetime risk of developing colon cancer in industrialized nations is 5%⁶. Currently, the treatment options for colon cancer is chemotherapy and surgery, of which the treatment response rate is 50%³. Due to the low response rate to treatment and high prevalence in developed societies, there is a significant research gap between current treatment options and the ability for improvement. Apoptotic resistance, like most other cancers, is one of the hallmarks of colon cancer⁶. Recent studies have focused on ERBB3, an EGFR tyrosine kinase inhibitor and upstream regulator of apoptosis that correlates with patient survival^7,10,12. In order to investigate this topic, various research papers published within the past 5 years were investigated. Papers indicating how ERBB3 is related to tumor size were noted and various potential therapies targeting ERBB3 and its significant effects on colon cancer research studies were also noted. Presenting the results of several journal articles allowed for the conclusion that ERBB3 plays a significant role in colon cancer. Inhibiting ERBB3 leads to a reduction in tumor size and increased cell cycle arrest in the G1 phase of the cell cycle⁸. Also, medications targeting ERBB3 lead to a decrease in tumor cell size over time¹¹. Antibodies such as seribantumab are monoclonal anti-ERBB3 antibodies that have demonstrated slowed tumor growth in multiple cancer types¹³. Another potential useful treatment is siRNA and miRNAs which target the post transcription protein synthesis of ERBB3 or other proteins in its pathway. HCT116 cell line of colon cancer cells has been shown to decrease proliferation when transfected with siERBB3⁷. miR-125 is also a tumor suppressor that downregulates metastasis in the overarching PI3K/Akt/mTOR3⁹. Transcriptional repressors, such as FOXD3, has also been shown to decrease proliferation of downstream targets of ERBB3¹⁴. Flavanols, such as Kaempferol, induces apoptosis by interfering with binding of ERBB3, reducing PI3K activity in a colon cancer cell line¹². The new research in regard to targeting ERBB3 provides potential new benefits to help increase the treatment efficacy in colon cancer.

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2. Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., and Sarkar, S. (2014). Drug resistance in cancer: an overview. Cancers, 6(3), p.1769- 1792.
3. Hu, T., Li, Z., Gao, C. Y., and Cho, C. H. (2016). Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World journal of gastroenterology, 22(30), p.6876.
4. Lee, H., Lee, H., Chin, H., Kim, K., and Lee, D. (2014). ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells. Oncotarget, 5(13), p.5138.
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7. Lee, H., Lee, H., Chin, H., Kim, K., and Lee, D. (2014). ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells. Oncotarget, 5(13), p.5138.
8. Zhang, J., Huang, K., O’Neill, K. L., Pang, X., & Luo, X. (2016). Bax/Bak activation in the absence of Bid, Bim, Puma, and p53. Cell death & disease, 7(6), p.2266.
9. Wang, J., Du, Y., Liu, X., Cho, W. C., & Yang, Y. (2015). MicroRNAs as regulator of signaling networks in metastatic colon cancer. BioMed research international.
10. Jardé, T., Kass, L., Staples, M., Lescesen, H., Carne, P., Oliva, K., … & Abud, H. E. (2015). ERBB3 positively correlates with intestinal stem cell markers but marks a distinct non proliferative cell population in colorectal cancer. PloS one, 10(9), e0138336.
11. Prasetyanti, P. R., Capone, E., Barcaroli, D., D’Agostino, D., Volpe, S., Benfante, A., … & Medema, J. P. (2015). ErbB-3 activation by NRG-1β sustains growth and promotes vemurafenib resistance in BRAF-V600E colon cancer stem cells (CSCs). Oncotarget, 6(19), p.16902.
12. Lee, H. S., Cho, H. J., Kwon, G. T., & Park, J. H. Y. (2014). Kaempferol downregulates insulin-like growth factor-I receptor and ErbB3 signaling in HT-29 human colon cancer cells. Journal of cancer prevention, 19(3), p.161.
13. Schoeberl, B., Kudla, A., Masson, K., Kalra, A., Curley, M., Finn, G., … & Fulgham, A. (2017). Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). NPJ systems biology and applications, 3, p.16034.
14. Li, K., Guo, Q., Yang, J., Chen, H., Hu, K., Zhao, J., … & Li, L. (2017). FOXD3 is a tumor suppressor of colon cancer by inhibiting EGFR-Ras-Raf-MEK-ERK signal pathway. Oncotarget, 8(3), p.5048.