RANK-pathway as a mediator of resistance to cyclin inhibitors and HER2-targeted therapies in breast cancer

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Expression of receptor activator of NFkB (RANK) drives stemness and resistance to therapy in ER+HER2- breast cancer

Publication . Fernandes Gomes, Inês; Almeida, Bernardo P. De; Dâmaso, Sara; Mansinho, André; Correia, Inês; Henriques, Sara; Duarte, Raquel; Vilhais, Guilherme; Félix, Pedro; Alves, Patrícia; Corredeira, Patrícia; Barbosa-Morais, Nuno; Costa, Luis; Casimiro, Sandra

The role of RANKL-RANK pathway in progesterone-driven mammary carcinogenesis and triple negative breast cancer tumorigenesis has been well characterized. However, and despite evidences of the existence of RANK-positive hormone receptor (HR)-positive breast tumors, the implication of RANK expression in HR-positive breast cancers has not been addressed before. Here, we report that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor (ER)-positive (ER+)/HER2- breast cancer cells, MCF-7 and T47D. Moreover, RANK overexpressing cells had a staminal and mesenchymal phenotype, with decreased proliferation rate and decreased susceptibility to chemotherapy, but were more invasive in vivo. In silico analysis of the transcriptome of human breast tumors, confirmed the association between RANK expression and stem cell and mesenchymal markers in ER+HER2- tumors. Importantly, exposure of ER+HER2- cells to continuous RANK pathway activation by exogenous RANKL, in vitro and in vivo, induced a negative feedback effect, independent of RANK levels, leading to the downregulation of HR and increased resistance to hormone therapy. These results suggest that ER+HER2- RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2- breast cancer cells, independently of RANK levels.

2020Journal article

Open access

c-Met expression in renal cell carcinoma with bone metastases

Publication . Silva Paiva, Rita; Fernandes Gomes, Inês; Casimiro, Sandra; Fernandes, Isabel; Costa, Luis

Hepatocyte growth factor (HGF)/c-Met pathway is implicated in embryogenesis and organ development and differentiation. Germline or somatic mutations, chromosomal rearrangements, gene amplification, and transcriptional upregulation in MET or alterations in autocrine or paracrine c-Met signalling have been associated with cancer cell proliferation and survival, including in renal cell carcinoma (RCC), and associated with disease progression. HGF/c-Met pathway has been shown to be particularly relevant in tumors with bone metastases (BMs). However, the efficacy of targeting c-Met in bone metastatic disease, including in RCC, has not been proven. Therefore, further investigation is required focusing the particular role of HGF/c-Met pathway in bone microenvironment (BME) and how to effectively target this pathway in the context of bone metastatic disease.

2020Journal article

Open access

RANK signaling pathway as a mediator of resistance to targeted therapies in breast cancer

Publication . Gomes, Inês Fernandes; Casimiro, Sandra Cristina Cara de Anjo; Costa, Luís António Marques da

Despite the efficacy of local treatments to control early breast cancer (BC) and great advances in the development of target therapies, relapse and progression rates are still high, mostly due to (neo)adjuvant systemic therapy resistance. Therefore, it is extremely important to unravel drivers of therapeutic resistance and devise strategies to overcome it. The receptor activator of nuclear factor-kB (RANK)-RANK ligand (RANKL) signaling pathway is a key regulator of several physiopathological processes, including osteoclastogenesis, breast carcinogenesis and BC progression. In this work, we provide the first characterization of RANK overexpressing (RANK OE) luminal BC, including its effect in response to standard of care therapies. We found that RANK OE luminal BC is characterized by a staminal and mesenchymal phenotype and decreased proliferation rate. Moreover, RANK OE cells were more invasive and less sensitive to chemo, endocrine and cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) therapy. Additionally, we disclose the mechanism(s) involved in RANK-mediated resistance to CDK4/6i and demonstrate that the pharmacological inhibition of RANK-RANKL pathway may improve the efficacy of this class of drugs. Major RANK-associated intrinsic or acquired resistance drivers were the decreased proliferation rate and chronic interferon γ-response activation, characteristic of luminal RANK OE cells and tumors. Importantly, RANKL inhibitors (RANKLi) restored sensitivity and prevented acquired resistance to CDK4/6i. Stemming from these findings, we also demonstrate that the genetic or pharmacologic inhibition of RANK-pathway improves the response to CDK4/6i of Rb-proficient TNBC, where current therapeutic options are mostly limited to chemotherapy. Overall, our results advanced the current knowledge about the role of RANK pathway in BC, clearly implicated in luminal BC biology. Moreover, this work has a strong translational value, showing that the use of RANKLi may span far beyond its current use in the clinics as a bone target therapy, and be repurposed as a new add-on to CDK4/6i in the treatment of metastatic luminal and TNBC patients.

2023-12Doctoral thesis

Embargoed access

The roadmap of RANKL/RANK pathway in cancer

Publication . Casimiro, Sandra; Vilhais, Guilherme; Fernandes Gomes, Inês; Costa, Luis

The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

2021Journal article

Open access