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dc.contributor.authorPalafox, M.
dc.contributor.authorMonserrat, L.
dc.contributor.authorBellet, M.
dc.contributor.authorVillacampa, G.
dc.contributor.authorGonzalez-Perez, A.
dc.contributor.authorOliveira, M.
dc.contributor.authorBrasó-Maristany, F.
dc.contributor.authorIbrahimi, N.
dc.contributor.authorKannan, S.
dc.contributor.authorMina, L.
dc.contributor.authorHerrera-Abreu, M. T.
dc.contributor.authorÒdena, A.
dc.contributor.authorSánchez-Guixé, M.
dc.contributor.authorCapelán, M.
dc.contributor.authorAzaro, A.
dc.contributor.authorBruna, A.
dc.contributor.authorRodríguez, O.
dc.contributor.authorGuzmán, M.
dc.contributor.authorGrueso, J.
dc.contributor.authorViaplana, C.
dc.contributor.authorHernández, J.
dc.contributor.authorSu, F.
dc.contributor.authorLin, K.
dc.contributor.authorClarke, Robert B
dc.contributor.authorCaldas, C.
dc.contributor.authorArribas, J.
dc.contributor.authorMichiels, S.
dc.contributor.authorGarcía-Sanz, A.
dc.contributor.authorTurner, N. C.
dc.contributor.authorPrat, A.
dc.contributor.authorNuciforo, P.
dc.contributor.authorDienstmann, R.
dc.contributor.authorVerma, C. S.
dc.contributor.authorLopez-Bigas, N.
dc.contributor.authorScaltriti, M.
dc.contributor.authorArnedos, M.
dc.contributor.authorSaura, C.
dc.contributor.authorSerra, V.
dc.date.accessioned2022-10-19T13:13:14Z
dc.date.available2022-10-19T13:13:14Z
dc.date.issued2022en
dc.identifier.citationPalafox M, Monserrat L, Bellet M, Villacampa G, Gonzalez-Perez A, Oliveira M, et al. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER(+) breast cancer. Nature communications. 2022 Sep 7;13(1):5258. PubMed PMID: 36071033. Pubmed Central PMCID: PMC9452562 reported receiving honoraria for speaker activities and advisory role from Pfizer, Novartis and Elli-Lilly and support for travel expenses from Roche and Pfizer. M.O. declares grant/research support (to the Institution) from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology, and Zenith Epigenetics; consultant role for Roche, GSK, PUMA Biotechnology, AstraZeneca, and Seattle Genetics; and has received honoraria from Roche, Seattle Genetics, and Novartis. G.V. reported receiving honoraria for speaker activities from MDS and advisory role from Astrazeneca. F.S. is employee of Novartis. K.L. is employee of Genentech. C.C. is a member of AstraZeneca’s External Science Panel, of Illumina’s Scientific Advisory Board, and is a recipient of research grants (administered by the University of Cambridge) from AstraZeneca, Genentech, Roche and Servier. J.A. has received research funds from Roche, Synthon, Menarini, and Molecular Partners and consultancy honoraria from Menarini. A.P. reports that his institution received research funding from Nanostring Technologies, Roche and Novartis and reports consulting and lecture fees from Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Elli-Lilly, MSD and PUMA. P.N. has consulted for Bayer, Novartis, and MSD and received compensation. R.D. is on advisory role of AstraZeneca, Roche and Boehringer-Ingelheim and has received speaker’s fees from Roche, Symphogen, IPSEN, Amgen, Servier, Sanofi, MSD, and research support from Merck. M.S. is on the scientific advisory board of Menarini Ricerche and the Bioscience Institute, has received research funds from Puma Biotechnology, Daiichi-Sankio, AstraZeneca, Targimmune, Immunomedics and Menarini Ricerche, and is a cofounder of Medendi.org. M.A. received a research grant from Eli-Lilly, honoraria from Novartis, Astrazeneca, Seattle Genetics, Abbvie and Pfizer and travel grants from Novartis, Roche, Pfizer. S.M. has provide punctual statistical advice to IDDI and Janssen Cilag and participated to data and safety monitoring committees of clinical trials (Hexal, Steba, IQVIA, Roche, Sensorion, Biophytis, Servier, Yuhan), outside the submitted work. C.S. has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Roche, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis Odonate Therapeutics, Pfizer, Philips He. C.Ve. & S.K. are founders of Sinopsee Therapeutics and Aplomex; neither company has any conflict with the current work. VHIO has had funding (paid directly to the Institution) from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon and Zenith Pharma. The remaining authors declare no competing interests. Epub 2022/09/08. eng.en
dc.identifier.pmid36071033en
dc.identifier.doi10.1038/s41467-022-32828-6en
dc.identifier.urihttp://hdl.handle.net/10541/625616
dc.description.abstractCDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.en
dc.language.isoenen
dc.relation.urlhttps://dx.doi.org/10.1038/s41467-022-32828-6en
dc.titleHigh p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER(+) breast canceren
dc.typeArticleen
dc.contributor.departmentExperimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spainen
dc.identifier.journalNature Communicationsen
dc.description.noteen]
refterms.dateFOA2022-10-24T12:11:15Z


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