Belgian scientists have shed light on the reason why particular types of cancers develop resistance to chemotherapy. By switching off the gene that produces a protein involved in chemotherapy resistance, they were able to make resistant cancer cells more sensitive to treatment.
Although new developments have been made in targeted therapies, chemotherapy remains the mainstay of cancer treatment. However, patients can develop a resistance to chemotherapy, causing cancer cells to evade its cancer-eradicating effects.
A process called epithelial-mesenchymal transition (EMT) has been shown to control cancer tumor development, progression, and metastasis, as well as resistance to chemotherapy. Through EMT, epithelial cancer cells lose their ability to adhere to neighboring cells, gaining increased migratory and invasive capabilities. But the mechanism by which EMT affects chemotherapy resistance is not well understood.
Researchers from the Université Libre de Bruxelles experimented on mice genetically modified to have skin squamous cell carcinoma (SCC), the second most common type of skin cancer. The researchers examined cancer cells presenting EMT to investigate the response different cell populations had to chemotherapy.
The mice were given the standard chemotherapy used to treat humans with metastatic SCC. The researchers found that the EMT-presenting cancer cells were very resistant to chemotherapy and that in the chemotherapy-resistant cells, expression of the RHOJ gene was high. The gene encodes a small GTP-binding protein that is also called RHOJ. GTP-binding proteins transmit signals outside the cell, causing intracellular changes.
Importantly, the researchers found that silencing RHOJ expression made the cancer cells sensitive to chemotherapy. Taking a closer look at the RHOJ protein, they discovered the mechanism by which RHOJ makes cells chemotherapy resistant. RHOJ was found to activate the DNA repair pathway in a cell after DNA damage was caused by chemotherapy. This allowed cancer cells to repair themselves and escape death.
The study has provided a greater understanding of the genetic mechanism underlying certain types of chemotherapy-resistant cancers, which has important ramifications for the development of future treatments.
“Our discovery that the inhibition of a single gene can make cancer cells sensitive to chemotherapy opens new avenues for the development of drugs targeting RHOJ that should decrease the resistance to chemotherapy in patients with cancers presenting EMT,” said Cédric Blanpain, corresponding author of the study.
The study was published in the journal Nature.
Source: Université Libre de Bruxelles via EurekAlert!