Co-Targeting Divergent Pathways in Colorectal Cancer
by epigene on May 9, 2017 - 9:27pm
Although statistics vary, colorectal cancer (CRC) is a major cause of cancer mortality in the United States and is the 2nd leading cause of death in men and the 3rd leading cause in women (American Cancer Society, 2017). At the forefront of colorectal cancer research is the study of the KRAS gene, which codes for proteins essential in regulating cell division. When KRAS contains or acquires mutations, it becomes deregulated, like an on/off switch that can’t be turned off. As a result, proteins essential for initiating growth factors, particularly epidermal growth factor (EGFR), are allowed to proliferate. This leads to increased “tissue signaling,” and cell proliferation that allows for the formation of cancerous cells and tumors.
This year, a research team in India isolated 40 cancerous patient tumor cells and segregated them based on tumors, which responded favorably with cancer drug certuximab and those that did not. Differing mutations in the KRAS gene did not seem to influence the cancer cells that did not respond to certuximab. Also, treatment with the drug often results in acquired resistance to it by metastatic (mCRC) tumors (Brijwani, et al, 2017). Clearly, more research was needed. The team identified two different signaling pathways that are significantly deregulated in the unresponsive tumor cells. The genes related to both these Notch and Erbb2 pathways play important roles in colon tumorigenesis and tumor cell proliferation.
The team tried using combinations of anti-EGFR and tumor inhibitor drugs on the non-responsive tumor cells but had little success. Eventually, they focused on inhibiting the two Notch and Erbb2 pathways with another combination of drugs and the team was largely successful. The tumors experienced cell death, a change in histology and a significant reduction of growth.
The research concluded that future cancer treatment would be increasingly individualized due to the complexity of individual pathways and gene mutations. However, establishing treatment protocols based on these complexities remains a daunting task.
I was drawn to this study because someone in my family has colorectal cancer and after chemo and radiation therapy and the removal of part of the colon, another (fast-growing) tumor was just found. The complexity of both how cancer grows and the ongoing technical research needed to understand and treat this cancerous complexity is awe-inspiring. Attempting to understand just some the technical terms and research methods took…a lot of research in just looking up what these words mean.
American Cancer Society. Key Statistics for Colorectal Cancer. © 2017 American Cancer Society, April 6th, 2017. Web: https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html
Brijwani N, Jain M, Dhandapani M, Zahed F, Mukhopadhyay P, Biswas M, Khatri D, Radhakrishna VD, Majumder B, Radhakrishnan P, Thiyagarajan S. Rationally co-targeting divergent pathways in KRAS wild-type colorectal cancers by CANscript technboogy reveals tumor dependence on Notch and ERbb2. Sci Rep. 2017 May 4;7(1):1502. doi: 10.1038/s41598-017-01566-x