dc.contributor.author | Guerrero-Zotano, Á | |
dc.contributor.author | Belli, S | |
dc.contributor.author | Zielinski, C | |
dc.contributor.author | Gil-Gil, M | |
dc.contributor.author | Fernandez-Serra, A | |
dc.contributor.author | Ruiz-Borrego, M | |
dc.contributor.author | Ciruelos Gil, EM | |
dc.contributor.author | Pascual, J | |
dc.contributor.author | Muñoz-Mateu, M | |
dc.contributor.author | Bermejo, B | |
dc.contributor.author | Margeli Vila, M | |
dc.contributor.author | Antón, A | |
dc.contributor.author | Murillo, L | |
dc.contributor.author | Nissenbaum, B | |
dc.contributor.author | Liu, Y | |
dc.contributor.author | Herranz, J | |
dc.contributor.author | Fernández-García, D | |
dc.contributor.author | Caballero, R | |
dc.contributor.author | López-Guerrero, JA | |
dc.contributor.author | Bianco, R | |
dc.contributor.author | Formisano, L | |
dc.contributor.author | Turner, N | |
dc.contributor.author | Martín, M | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-05-02T09:11:51Z | |
dc.date.available | 2023-05-02T09:11:51Z | |
dc.date.issued | 2023-04-14 | |
dc.identifier | 716446 | |
dc.identifier.citation | Clinical Cancer Research, 2023, 29 (8), pp. 1557 - 1568 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5770 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.CCR-22-2206 | |
dc.description.abstract | PURPOSE: In hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed. EXPERIMENTAL DESIGN: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. RESULTS: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET. CONCLUSIONS: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i. | |
dc.format | Print | |
dc.format.extent | 1557 - 1568 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.ispartof | Clinical Cancer Research | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.subject | Humans | |
dc.subject | Female | |
dc.subject | Breast Neoplasms | |
dc.subject | Capecitabine | |
dc.subject | Receptor, ErbB-2 | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Proto-Oncogene Proteins | |
dc.subject | Cyclin-Dependent Kinase 4 | |
dc.subject | RNA, Messenger | |
dc.subject | Oncogene Proteins | |
dc.subject | Cyclin E | |
dc.title | CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-02-02 | |
dc.date.updated | 2023-05-02T09:09:36Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1158/1078-0432.CCR-22-2206 | |
rioxxterms.licenseref.startdate | 2023-04-14 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36749874 | |
pubs.issue | 8 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1158/1078-0432.ccr-22-2206 | |
pubs.volume | 29 | |
icr.researchteam | Molecular Oncology | |
dc.contributor.icrauthor | Pascual, Javier | |
dc.contributor.icrauthor | Turner, Nicholas | |
icr.provenance | Deposited by Mr Arek Surman (impersonating Prof Robert Huddart) on 2023-05-02. Deposit type is initial. No. of files: 1. Files: 1557.pdf | |