A group of researchers from Brazil and Portugal has uncovered the molecular changes that indicate the resistance of head and neck tumors to cetuximab, one of the few treatments approved for this type of cancer. About 60% of patients do not respond well to treatment.
With the results, published in the journal Cells, It is expected that soon doctors will be able to predict which patients will or will not respond to treatment, which is considered liqueur. Based on the results, the researchers also suggest testing combinations of cetuximab with other drugs to make the resistance to the substance.
“Treatment for head and neck tumors has evolved relatively little and still includes surgery, radiation and chemotherapy. Cetuximab is revolutionary, as it is a specific cellular receptor therapy that varies significantly in these tumors, known by the acronym EGFR.” , He explains. Roy Manuel Rice, a researcher at De Amor Hospital – formerly known as the Artus Cancer Hospital – and the University of Minho, Portugal.
Until then it was not known what caused drug resistance in some patients with head and neck tumors. This is a crucial factor in deciding how to treat them. In addition, the inability to predict the cost of treatment at a high cost means that it is not included in the list of drugs covered by the United Health System (SUS) for this type of cancer.
However, cetuximab is customized to treat metastatic colorectal cancer, as there are genetic tests for mutations in genes. KRAS, NRAS and BRAF The predictors are drug resistance. The drug is only given to patients who have the potential to respond positively.
The study now published paves the way for the development of customized approaches to head and neck tumors as well.
“We analyzed resistant strains – at the level of DNA, RNA and proteins – and found some highly expressed biological markers, such as mTOR protein. Our proposal is also to use cetuximab combination regimens with drugs that inhibit these expressed proteins, and make it a phenotype of resistance, ”says Isabella Faria Gomes, who did the work during her doctorate at De Amor Hospital with a grant from FAPESP.
Currently, there are specific inhibitors of the protein and mTOR pathway in the market. Thus, the protein expressed in the resistant strain can be inhibited in regimens combined with other drugs acting on other proteins in the same signaling pathway of the cell.
Durable varieties
To discover the response mechanisms to the drug that may occur, the Barretos group developed a model in vitro To mimic the resistance that occurs in patients’ tumors.
A strain of head and neck tumor is initially sensitive to the drug, cultured in the laboratory and “shelled” for a year with cetuximab. The surviving cells, i.e. those that developed resistance, were then analyzed by the researchers using a number of molecular tools so that they could understand what made them different.
“We put selective pressure on this tumor lineage. The longer it was exposed to the drug, the more resistant it became. All the molecular changes became more visible,” reports Renato da Silva Oliveira, a researcher who developed the method during his doctorate at the Center for Molecular Oncology Research At De Amor Hospital, under the guidance of Rice.
The model of resistance created by the researchers is now being developed in collaboration with the Institute of Energy and Nuclear Research (Ipen) and the University of Alabama, in the United States.
In the future, it may lead to a specific test to detect resistance of head and neck tumors to the drug. If it progresses to this stage, the study may be conducted in collaboration with the AC Camargo Cancer Center, in Sao Paulo, where some patients are being treated with cetuximab.
The next step in the study is to validate the findings in animal models and in patients who are not resistant to Cetuximab treatment. Furthermore, in future studies, combination regimens between cetuximab and other therapeutic drugs may be tested.
the article Comprehensive molecular landscape of cetoxymab resistance in head and neck cancer cell lines Can be read at: www.mdpi.com/2073-4409/11/1/154/htm.