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

2023-12Doctoral thesis Embargoed access
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datacite.subject.fosCiências Médicas::Ciências da Saúdept_PT
dc.contributor.advisorCasimiro, Sandra Cristina Cara de Anjo
dc.contributor.advisorCosta, Luís António Marques da
dc.contributor.authorGomes, Inês Fernandes
dc.date.accessioned2024-05-24T11:13:13Z
dc.date.embargo2027-01
dc.date.issued2023-12
dc.date.submitted2023-09
dc.description.abstractDespite 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.pt_PT
dc.identifier.tid101599617pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/64865
dc.language.isoengpt_PT
dc.relationRANK-pathway as a mediator of resistance to cyclin inhibitors and HER2-targeted therapies in breast cancer
dc.relationPhysiopathology and clinical implications of the RANK c.1386C>T (R450W) mutation in breast cancer patients
dc.subjectcancro da mama (CM)pt_PT
dc.subjectresistência à terapiapt_PT
dc.subjectvia de sinalização do recetor ativador do fator nuclear-kB (RANK)pt_PT
dc.subjectinibidores de cinases dependentes de ciclina 4 e 6 (iCDK4/6)pt_PT
dc.subjectinibidores do ligando do RANK (iRANKL)pt_PT
dc.subjectbreast cancer (BC)pt_PT
dc.subjecttherapy resistancept_PT
dc.subjectreceptor activator of nuclear factor-kB (RANK) signaling pathwaypt_PT
dc.subjectcyclin dependent kinase 4 and 6 inhibitors (CDK4/6i)pt_PT
dc.subjectRANK ligand inhibitors (RANKLi)pt_PT
dc.titleRANK signaling pathway as a mediator of resistance to targeted therapies in breast cancerpt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitleRANK-pathway as a mediator of resistance to cyclin inhibitors and HER2-targeted therapies in breast cancer
oaire.awardTitlePhysiopathology and clinical implications of the RANK c.1386C>T (R450W) mutation in breast cancer patients
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F139178%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F28636%2F2017/PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsembargoedAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication93611b64-0e0d-48b0-8c45-920f7c845b48
relation.isProjectOfPublicationc94dfe35-50fb-443d-8aae-d8207d0da300
relation.isProjectOfPublication.latestForDiscoveryc94dfe35-50fb-443d-8aae-d8207d0da300
thesis.degree.nameTese de doutoramento, Ciências Biomédicas (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Medicina, 2023pt_PT

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