Chemotherapy remains the most widely used treatment for advanced-stage cancer. But it is common for tumors to become resistant, which worsens the prognosis. Researchers from the Free University of Brussels and the DNA Replication Group of the CNIO (National Center for Oncological Research) have discovered one of the reasons why some types of cancer become resistant to chemotherapy, and present their results in «Nature ».
Cancers of the epithelia, which are the tissues that cover all surfaces of the body -the skin, but also the lining of the organs-, are related to a type of change that epithelial cells undergo, called the epithelial-mesenchymal transition. In this process, cells break away from their neighbors and acquire invasive properties, which help them colonize surrounding tissues and spread throughout the body.
It was known that the epithelial-mesenchymal transition also plays a role in tumors becoming resistant to chemotherapy, but exactly why was unknown. The new result points to a protein called RHOJ. The work, led by the researcher Cédric Blanpain, from the Free University of Brussels, has as co-authors the CNIO researchers Sara Rodríguez-Acebes and Juan Méndez.
The researchers observed, in mouse models of skin cancer, that the expression of the RHOJ protein is especially high in cells resistant to chemotherapy. And they showed that when this protein stops expressing itself, cancer cells are vulnerable to chemotherapy. In other words, inhibiting the RHOJ protein makes the cancer cells respond to treatment again.
Inhibiting the RHOJ protein makes cancer cells respond to treatment again
The authors show that RHOJ triggers the formation of long actin protein filaments and promotes the repair of chemotherapy-induced DNA damage. This helps the cancer cell survive the treatment.
“It has been very interesting to discover that resistance to chemotherapy in TMS cancers is partly controlled by DNA replication and repair mechanisms,” says Méndez. “This is another example of how basic research on these cellular processes allows us to address a problem with major clinical implications.”
“The fact that inhibiting RHOJ reverses the resistance of cancer cells to chemotherapy opens the possibility of developing drugs against RHOJ to improve the efficiency of treatment in patients with these types of metastatic cancer,” adds Juan Méndez.