Breast cancer cells

A new study suggests an already approved drug, denosumab (Amgen’s Prolia/Xgeva), could work in combination with standard care to improve outcomes in metastatic cases of the most common type of breast cancer. RANK ligand inhibition, their research suggests, could make patients with luminal breast cancer less resistant to standard care. This could create a new market for denosumab, already a leading drug for osteoporosis.

This work was led by Sandra Casimiro, staff scientist at the Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal), and Luís Costa, principal investigator at the iMM and oncologist at the Hospital Santa Maria. It was recently published in Cell Reports Medicine.

Breast cancer is a heterogeneous disease, but 70% of cases are characterized by the presence of hormone receptors for estrogen, progesterone, or both. This subtype of the disease is called luminal breast cancer. The first line of treatment when such patients develop metastatic disease is endocrine therapy in combination with CDK4/6 inhibitors. But this treatment either fails right away or eventually.

“The first-line of care treatment for metastatic luminal breast cancer… is the combination of endocrine therapy with CDK4/6 inhibitors. Although this treatment was a life-changing discovery for breast cancer patients, around 20% are irresponsive and the majority of the ones who respond to treatment becomes resistant within 2 years,” said Costa, co-leader of the study.

There has long been evidence that the RANKL/RANK signaling system is associated with nearly each step in breast cancer development, from primary oncogenesis to the establishment of secondary tumors in the bone.

Denosumab is a human IgG2 monoclonal antibody for RANKL that was initially approved  in 2010 for osteoporosis. The next year it was also approved for breast cancer patients taking aromatase inhibitors, which make patients susceptible to bone fractures. Denosumab binds to RANKL and then prevents it from interacting with RANK, thereby decreasing osteoclast differentiation and activation, which consequently reduces bone resorption.

“We studied the possibility that the RANK signaling pathway, which is an important mediator of breast cancer aggressiveness in triple negative cancer, could be relevant in the resistance to treatment in the case of luminal breast cancer,” said Casimiro.

The team found that high levels of RANK in cancer cells are associated with resistance to treatment with CDK4/6 inhibitors. They analyzed samples of tumors from patients treated with CDK4/6 inhibitors, and found that the levels of RANK in the tumor, “Increase overtime during the duration of the treatment,” Casimiro explained.

“This suggests that RANK can be implicated in acquired resistance as well,” she added. “Having this in mind, we tested in vitro and in mouse models if inhibiting the RANK pathway in combination with the current therapy would improve treatment efficacy, and found that the cancer cells respond better to the treatment in the presence of RANK ligand inhibitors.”

Donosumab could also be a cost-effective option. Prolia is approved and marketed in more than 80 countries worldwide. Its patents expired in some European markets this June. It is still protected in France, Italy, Spain, and the US, until 2025.

“The pharmacological inhibition of RANK pathway is already used in the clinical setting. Our study suggests that combination therapy with RANK ligand inhibitors and the current standard care for metastatic luminal breast cancer could improve the outcome in non-responsive patients and avoid or delay the resistance to treatment,” said Costa.

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