The research opens up new ways to overcome treatment resistance in colorectal cancer

The research opens up new ways to overcome treatment resistance in colorectal cancer

Colon cancer is one of the most common types of cancer. His treatment is mainly based on chemotherapy. However, over time, chemotherapy induces resistance in the majority of patients, who eventually stop responding to the drugs. As a result, the five-year survival rate of those affected is still low. After managing to reproduce this resistance in the laboratory, a team from the University of Geneva (UNIGE) has found a way to overcome it. The team used an optimized combination of drugs that belong to the class of tyrosine kinase inhibitors, which attack cancer cells in ways other than chemotherapy. These findings, found in the journal Cancers, open new avenues for overcoming treatment resistance and developing new therapies that are more targeted than chemotherapy.

Colorectal cancer is the third most commonly diagnosed cancer in the world and second only to lung cancer in terms of mortality. It most commonly develops in the end section of the large intestine after the age of 50. It results from a change in the DNA of certain cells present in that organ. These cells become cancerous and multiply uncontrollably until they form a primary tumor. As with many cancers, these cells can migrate to other parts of the body and form secondary tumors. This is called metastatic cancer.

While genetics play a role in the development of the disease, the presence of inflammatory bowel disease (e.g. Crohn's disease) and certain dietary habits (alcohol, red meat) are also risk factors. In the case of a primary tumor, treatment is based on surgery and chemotherapy. For second tumors, it is based on a combination of chemotherapy. These treatments are non-targeted and aggressive. They cause significant side effects. They also lead to progressive resistance to treatment in the majority of patients.

The phenomenon reproduced in the laboratory

A UNIGE team led by Patrycja Nowak-Sliwinska, associate professor at the School of Pharmaceutical Sciences at the Faculty of Natural Sciences at UNIGE, has managed to study precisely this resistance phenomenon in cancer cells. The team has also discovered a way to overcome it by using a combination of tyrosine kinase inhibitors. Tyrosine kinases enable the transport of a phosphate group to a key protein for cell division and growth. With a specific mixture of inhibitor molecules, these enzymes are “blocked” and this transport is interrupted. The proliferation of tumor cells is then stopped or slowed down.

To make this discovery, the UNIGE team used cancer cell lines from different patients. After growing these cells in the lab, they chronically exposed them to FOLFOXIRI, the most common chemotherapy combination used to treat colorectal cancer. “After about 34 to 50 weeks of exposure, we managed to maintain in vitro this phenomenon of acquired chemoresistance, as we observe in a clinical situation,” explains Patrycja Nowak-Sliwinska, the last author of the study.

Take an alternative path

The scientists then noticed that the resistant cells showed a desensitization of the plasma membrane, i.e. their envelope, which had become less permeable to the molecules from the chemotherapy drugs. They therefore do not penetrate these cells or no longer penetrate them sufficiently. Still within this membrane, the researchers observed a deregulation of certain genes responsible for the lipid circulation networks that need to be specified.

We then exposed the resistant cells to a combination of tyrosine kinase inhibitors that had previously been optimized in our laboratory. We found that they were able to overcome this resistance by taking a different “path” than the one that chemotherapy molecules use to signal the cell.”

George M. Ramzy, Ph.D. Student, Faculty of Pharmaceutical Sciences, Faculty of Science, UNIGE and first author of the study

The research team managed to block up to 82% of the metabolic activity of these cells - i.e. their energy supply - and thus significantly weaken them. This discovery opens new avenues to overcome the resistance phenomenon in colorectal cancer, which is responsible for the low five-year survival rate of patients. "In addition to overcoming resistance, this treatment has the advantage of having a targeted effect. Its effect is specific to tumor cells, which is not the case with chemotherapies, which act aggressively on a broader spectrum of cells," concludes Patrycja Nowak-Sliwinska.

Source:

University of Geneva

Reference:

Ramzy, GM, et al. (2022) FOLFOXIRI resistance induction and characterization in human colon cancer cells. Cancer. doi.org/10.3390/cancers14194812.

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