New combination therapy for hormone responsive metastatic breast cancer

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New combination therapy for hormone responsive metastatic breast cancer

Quinta, 27.07.2023

Breast cancer is a heterogeneous disease, but 70% of cases are characterized by the presence of hormone receptors for estrogen, progesterone, or both. The first line of treatment for these patients, when presenting with metastatic disease, is endocrine therapy in combination with CDK4/6 inhibitors, but the majority develops resistance to treatment within two years. Now, a new study 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 (Portugal), and published today in the scientific journal Cell Reports Medicine*, found a promising molecular target in cancer cells that could be used in combination with the standard care to avoid resistance to treatment in metastatic breast cancer. “Currently, the first-line of care treatment for metastatic luminal breast cancer, which expresses receptors for estrogen and/or progesterone, 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”, says Luís Costa, oncologist and co-leader of the study. “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”, explains Sandra Casimiro, co-leader of the study and researcher at iMM. “In this study, we found that high levels of RANK in cancer cells are associated to resistance to treatment with CDK4/6 inhibitors. By analyzing a dataset of human samples of tumors from patients treated with CDK4/6 inhibitors, we found that the levels of RANK in the tumor increase overtime during the duration of the treatment. This suggests that RANK can be implicated in acquired resistance as well”, continues Sandra Casimiro, adding: “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”. “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”, concludes Luís Costa, on the clinical relevance of these findings. Upon clinical studies, RANK ligand inhibition could represent a promising add-on to the current standard care treatment for hormone responsive breast cancer. This work was developed at iMM in collaboration with the Oncology from the Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (Portugal), and with researchers from the Spanish National Cancer Research Centre (Spain), and the Bellvitge Biomedical Research Institute (Spain). This study was funded by the Portuguese Foundation for Science and Technology (FCT).

Inês Gomes1, Lina M Gallego-Paez1, Maria Jiménez2, Patricia G Santamaria2, André Mansinho3,#, Rita Sousa3, Catarina Abreu3, Eva González Suárez2,4, Luis Costa1,3,5,* and Sandra Casimiro1,5,6,*

1Luis Costa Laboratory, Institute of Molecular Medicine (iMM), Lisbon Medical School, 1649-028 Lisbon, Portugal

2Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain

3Oncology Division, Hospital de Santa Maria-CHULN, 1649-028 Lisbon, Portugal

4Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain

5Senior author 6Lead contact #Current affiliation: START Lisbon, 1649-028 Lisbon, Portugal

The combination of endocrine therapy (ET) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) was a hallmark in metastatic luminal breast cancer (BC). However, intrinsic and acquired resistance affects long-term efficacy. Here, we study the role of the receptor activator of nuclear factor-κB (RANK) pathway in CDK4/6i resistance. We find that RANK overexpression in luminal BC is associated with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts, and decreased proliferation rate and chronic interferon (IFN) γ response are highlighted as resistance drivers. Gene expression data from the NeoPalAna CDK4/6i clinical trial, and studies with palbociclib-resistant cell lines, show that RANK is upregulated after treatment with CDK4/6i, supporting a role in acquired resistance. Our study shows that RANK ligand (RANKL) inhibitors can restore sensitivity to CDK4/6i and prevent acquired resistance. On the basis of these findings, we conclude that pharmacological inhibition of the RANK pathway through RANKL blocking could represent an add-on to ET + CDK4/6i, warranting further clinical studies.

Cell Reports Medicine