Overcoming drug resistance to colon cancer treatments

Colorectal cancer is one of the
most common cancers.
Its treatment is mainly chemotherapy
.
However, over time, chemotherapy develops resistance in most patients, eventually leading to a non-response
to the drug.
As a result, 5-year survival rates for affected populations remain low
.
A team of researchers at the University of Geneva has found a way
to overcome this resistance after successfully replicating it in the laboratory.
The team used an optimized combination of tyrosine kinase inhibitors that attack cancer cells
through a different pathway than chemotherapy.
The results, which will be published in the journal cancer, open new avenues
for overcoming treatment resistance and developing new therapies that are more targeted than chemotherapy.

In terms of mortality, colorectal cancer is the third most diagnosed cancer in the world, after lung cancer
.
It most often occurs at the end of the colon at the age of
50.
It is due to changes
in the DNA of certain cells present in this organ.
These cells become cancerous and proliferate in an uncontrolled manner until a primary tumor
is formed.
Like many cancers, these cells can migrate to other parts of the body to form secondary tumors
.
This is known as metastatic cancer
.

While genetics play a role in the development of the disease, inflammatory bowel disease (such as Crohn's disease) and certain dietary habits (alcohol, red meat) are also risk factors
.
In the case of primary tumors, treatment is based on surgery and chemotherapy
.
In the case of secondary tumors, it is based on a combination of
chemotherapy.
These treatments are non-targeted and aggressive
.
They can have serious side effects
.
They also lead to progressive resistance to treatment in most patients
.

This phenomenon is reproduced in the laboratory

A UNIGE team led by Patrycja Nowak-Sliwinska, an associate professor at UNIGE's School of Science, has successfully studied this resistance phenomenon
precisely in cancer cells.
The team also found a way to overcome it
by using a combination of tyrosine kinase inhibitors.
Tyrosine kinases allow phosphate groups to transport to key proteins
for cell division and growth.
In a specific mixture of inhibitor molecules, these enzymes are "blocked" and this transport is interrupted
.
The proliferation of tumor cells then stops or slows
down.

To make this discovery, the team at the United Nations Institute for Medical Research used cancer cell lines
from different patients.
AFTER ALLOWING THESE CELLS TO PROLIFERATE IN THE LAB, THEY EXPOSED THEM TO FOLFOXIRI, THE MOST COMMON CHEMOTHERAPY COMBINATION
FOR COLORECTAL CANCER.
Patrycja Nowak-Sliwinska, the last author of the study, explains: "After about 34 to 50 weeks of exposure, we managed to acquire this phenomenon of acquired chemical resistance in vitro, as we observed in clinical situations
.
"

Go the other way

The scientists then noticed that drug-resistant cells showed plasma membrane desensitization, their envelope, which has reduced
permeability to molecules from chemotherapy products.
As a result, they cannot or no longer penetrate these cells
adequately.
Inside this membrane, the researchers observed dysregulation of certain genes responsible for the lipid cycling network, which must be determined
.

"We then exposed the resistant cells to a
combination of tyrosine kinase inhibitors that our lab had previously optimized.
We note that they make it possible to overcome this resistance by adopting another 'pathway' than the one that chemotherapy molecules use to signal cells," said George M.
Ramzy, lead author of the study and a doctoral student at the Faculty of Pharmacy at the Faculty of Science, United
Nations University.

The team succeeded in blocking up to 82 percent of the cells' metabolic activity, their energy supply, which greatly weakened them
.
This finding opens up new avenues to overcome colorectal cancer drug resistance, which is responsible for
the low 5-year survival rate of patients.
"In addition to overcoming drug resistance, the advantage of this treatment is that it is targeted
.
Its action is directed against tumor cells, unlike chemotherapy, which has a positive effect on a wider range of cells," concludes Patrycja Nowak-Sliwinska
.