Approved drug could help overcome resistance to primary treatment against metastatic breast cancer

Brest cancer is the most common cancer in women. Among breast tumors that spread to other organs (develop metastasis), 70% belong to a variant, called luminal, whose cells are sensitive to the female sex hormones estrogen and progesterone. In fact, the tumor forms when these hormones order the cells to divide. The usual treatment for advanced cases is surgery, followed by hormone therapy, alone or in combination with chemotherapy or targeted therapy.

Targeted therapies target specific molecules in the tumor. In luminal breast cancer, targeted therapy inhibits CDK4/6 proteins, which control growth rate and division of cells. The approval of these inhibitors was a breakthrough in the treatment of luminal breast cancer.

Resistance to the most effective treatment

Yet 20% of patients do not respond to treatment. And most of those who do respond develop resistance within the first two years, which diminishes the effects of the therapy.

Researchers Luís Costa y Sandra Casimiro, at the Instituto de Medicina Molecular João Lobo Antunes (iMM, Portugal) and Eva González Suárez, at the Spanish National Cancer Research Center (CNIO), have discovered one of the mechanisms leading to mentioned resistance and propose an option to fight them. Their study is published in Cell Reports Medicine.

The research focuses on the RANK protein, known to be involved in the cell renewal process in our bones. "Previous research by our group and other authors had already shown that RANK also plays a role in breast cancer, both in tumor initiation and progression," González Suárez, chief of the Transformation and Metastasis Group, says.

In this new study, IMM and CNIO researchers have shown that high levels of RANK in tumor cells promotes resistance to CDK4/6 inhibitors. Further, it affects an important tool the immune system uses to fight tumors, interferon gamma. Consequently, patients with high levels of RANK protein are not only left without a natural defense of their bodies, but also cease to respond over time to the more common and effective treatment.

A drug approved for osteoporosis

These results have clinical value. On the one hand, a patient's RANK levels could help decide if inhibitors of CDK4/6 would be a treatment option for her. On the other hand, further research could be carried out towards complementing combined hormone and targeted therapy with a third drug aimed to block the action of RANK and overcome resistance.

The study proposes the drug denosumab, a monoclonal antibody approved in the United States and Europe to treat osteoporosis and prevent metastasis to the bones and skeletal damage from other cancers.

"Its advantage is that, because it is already approved, we know a lot about its safety profile. We are aware of its potential side effects, which can be considered as minor in a cancer context. Therefore, from a research perspective, a clinical trial with patients could be designed at once," González Suárez remarks.

That would be the next step towards the application of their results. "This is the obvious move. For the paper we have worked only with cell lines and mice models without an immune system, which is very important. The clinical trials with patients would confirm whether there is a real benefit from adding denosumab to the combined hormone and CDK4/6 inhibitors therapy."

Gomes I, Gallego-Paez LM, Jiménez M, Santamaria PG, Mansinho A, Sousa R, Abreu C, Suárez EG, Costa L, Casimiro S.
Co-targeting RANK pathway treats and prevents acquired resistance to CDK4/6 inhibitors in luminal breast cancer.
Cell Rep Med. 2023 Jul 13:101120. doi: 10.1016/j.xcrm.2023.101120