Discovery of one of the Mechanisms that Generate Resistance to Chemotherapy

CNIO has identified a new factor that is decisive in resistance to chemotherapy.

USA – A research study published in the journal Molecular Cell (Elsevier) highlights the importance of both cellular composition and intercellular communication to define the behavior of tumors, which is a new step in understanding how cells of cancer develop resistance to drugs.

A group of researchers from the US Massachusetts Institute of Technology (MIT), Harvard University and the Institute for Cancer Dana-Farber used sequential technology from a single cell to examine the entire spectrum of cell types present in metastatic melanoma.

“Like other solid tumors, melanomas are ecosystems that contain not only malignant tumor cells, but also non – malignant cells such as fibroblasts and a variety of immune cells,” stated in the published research work.

Scientists analyzed malignant profiles 4645, immune and connective tissue cells isolated from tumors of 19 patients with metastatic melanoma and identified 229 genes with increased expression in malignant cells in a region compared to other regions of the tumor.

Therefore, the researchers concluded that it is vital to understand the behavior of a tumor by observing its cellular composition and intercellular communication.

During the study, the scientists tried to anticipate possible resistance to treatment that may arise.

Editing genomes

To identify possible mutations that can make cells resistant to inhibitors of ATR, the researchers used a technology to alter the CRISPR genome, a tool that allows you to “cut” and “paste” fragments of the human genome. CRISPR sequences (clustered regularly interspaced short palindromic repeats). The tool that earned the two creators, Emmanuelle Charpentier (France) and Jennifer Doudna (USA), the Princess of Asturias Award last year.

Using this technology, they created a collection of cells in which each had a different gene mutated.

Subjecting cells to inhibition of ATR could isolate some treatment-resistant and subsequently carrying identification of the mutation.  It showed that cells with mutations in the gene survived CDC25A.

“CDC25A is a protein that usually highly expressed in tumors,” Fernandez-Capetillo explained.

“This work suggests a way to identify patients who respond better to treatment is to determine those in which the levels of this protein in the tumor are higher,” he adds.

In addition to finding a mutation that makes cells resistant to treatment, researchers also identified a treatment that could eliminate the resistant cells.

Rights to develop drugs based on ATR kinase inhibitors developed at the Spanish National Cancer Research Centre (CNIO) protein are owned by Merck. The Centre had reached an agreement in 2013 in exchange for potential revenue of 19 million Euros.

Source: CNIO

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