A group that brings together researchers from Brazil and Portugal has unveiled the molecular changes that indicate the resistance of head and neck tumors to cetuximab, one of the few therapies approved for this type of cancer. About 60% of patients do not respond well to treatment.
With the results, published in the review cells, it is expected that doctors will soon be able to predict which patients will or will not respond to the treatment, considered expensive. Based on the results, the researchers also suggest testing combinations of cetuximab with other drugs to reverse resistance to the agent.
“Treatment of head and neck tumors has evolved relatively little and still relies primarily on surgery, radiotherapy and chemotherapy. Cetuximab is revolutionary because it is a specific therapy for a cell receptor significantly altered in these tumors, known by the acronym EGFR,” he explains. Rui Manuel Reisresearcher at Hospital de Amor – formerly known as Hospital do Câncer de Barretos – and University of Minho, Portugal.
Until then, it was not known what caused drug resistance in a portion of patients with head and neck tumors. This is a decisive factor in deciding how to deal with them. In addition, the inability to predict the success of an expensive treatment means that it is not included in the list of drugs covered by the Unified Health System (SUS) for this type of cancer.
However, cetuximab is used in a personalized way to treat metastatic colorectal cancer because there are genetic tests for mutations in genes kras, NRAS e BRAF that predict drug resistance. The drug is given only to patients who are likely to react positively.
The published study now paves the way for the development of personalized approaches for head and neck tumors as well.
“We analyzed resistant strains – at the DNA, RNA and protein level – and found highly expressed biomarkers, such as the mTOR protein. Our proposal is also to use combination treatment regimens with cetuximab with drugs that inhibit these expressed proteins, reversing this resistance phenotype,” says Izabela Faria Gomeswho carried out the work during his doctorate at the Hospital de Amor with if of FAPESP.
Currently, there are specific inhibitors of the protein and of the mTOR pathway on the market. Thus, the protein that is expressed in the resistant strain could be inhibited in combination regimens with other drugs that act on other proteins in the same cell signaling pathway.
resistant strains
To uncover the drug-response mechanisms that may occur, Barretos’ group developed a model in vitro to mimic the resistance that occurs in patient tumors.
An initially drug-responsive head and neck tumor strain was grown in the lab and “bombarded” for a year with cetuximab. The cells that survived, that is, those that developed resistance, were then analyzed by the researchers using several molecular tools to understand what made them different.
“We applied selective pressure to this tumor line. As it was exposed to the drug longer, it became more resistant. All the molecular alterations became more visible,” reports Renato da Silva Oliveira, researcher who developed the method during of his doctorate at the Molecular Oncology Research Center of the Hospital de Amor, under the supervision of Reis.
The resistance model created by the researchers is currently being developed in partnership with the Institute for 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 the resistance of head and neck tumors to the drug. If it progresses to this stage, the study could be carried out in partnership with the AC Camargo Cancer Center, in São Paulo, where some patients are treated with cetuximab.
The next step in the research is to validate the results in animal models and in patients refractory to cetuximab treatment. Moreover, in future studies, therapeutic combinations between cetuximab and other therapeutic agents could be tested.
The article Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines can be read at: www.mdpi.com/2073-4409/11/1/154/htm.
This text was originally published by FAPESP Agency according to Creative Commons license CC-BY-NC-ND. read it original here.