Study finds link between high copy number of chromosomal region and resistance to chemotherapeutic drugs

Researchers from the Bellvitge Biomedical Research Institute (IDIBELL), with the participation of collaborators from Baylor College of Medicine (Houston) and the Asturian University Institute of Oncology (IUOPA), publish today At Research against cancer a study in which they associate the high copy number of a chromosomal region with the emergence of resistance to a chemotherapeutic drug. The research was led by Dr. Eva González-Suárez, leader of the transformation and metastasis group at IDIBELL.

Nowadays, chemotherapy, despite its side effects, remains the most effective treatment for cancer. Docetaxel, a chemical compound that acts on tumor cells and prevents their correct division, is one of the most common chemotherapy drugs in the study. The research project focuses on the most aggressive subtype of breast cancer: triple negative breast cancer (TNBC). This subgroup is characterized by being quite heterogeneous (which is why there is no targeted treatment to combat it) and is generally associated with a poor prognosis. Despite promising initial responses to chemotherapy, drug resistance often develops during treatment. One of the challenges that oncologists face is the choice of chemotherapy drug that will benefit patients with triple-negative breast cancer. This selection is made in most cases arbitrarily.

To carry out this study, scientists worked with patient-derived xenografts (PDX). These PDXs are animal models (mice) in which tumor cells of the patient have been implanted, so that the tumor sample is much more representative than a conventional cell culture. These models can be used to test the efficacy of drugs and to study the emergence processes of drug resistance, that is, to understand how tumor cells no longer respond to treatments.

In analyzing the effect of docetaxel on triple negative breast cancer on PDX, the researchers found that, as in patients, docetaxel resistance occurs during treatment and compared the genome of paired tumors sensitive to docetaxel and their equivalents having developed resistance to continuous exposure to the drug. They identified an increase in the number of copies of a region of chromosome 12, called chr12p, in tumors resistant to docetaxel and even after short treatments with docetaxel. These results imply that a subpopulation of docetaxel-resistant tumor cells is present in tumors and survives the drug, unlike others that die during treatment.

In addition, researchers have found that this subpopulation containing multiple copies of docetaxel-resistant chr12p is very vulnerable to treatment with another chemotherapeutic drug, carboplatin, which is why Dr. González-Suárez proposes "d". apply sequential treatment combining docetaxel and then carboplatin, instead of using the two drugs individually or simultaneously, as is currently done. "

"We have associated the presence of this amplified chr12p chromosomal region with the emergence of resistance to docetaxel and carboplatin susceptibility," said Dr. Eva González-Suárez. "We propose that the number of copies of chr12p be considered as a biomarker for predicting whether patients' tumors will develop docetaxel resistance or, more importantly, once docetaxel resistance appears, have an alternative drug to treat patients., carboplatin.

This discovery could represent the first description of a biomarker for chemotherapy drug selection and the sequence of treatments that may benefit patients with triple negative breast cancer.