1. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
- Author
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Stefan Michiels, Cristina Saura, Cristina Viaplana, Marta Palafox, Abel Gonzalez-Perez, Alejandra Bruna, Paolo Nuciforo, Marta Guzman, Arribas Joaquín, Meritxell Bellet, Alicia García-Sanz, Violeta Serra, Faye Su, Olga Rodriguez, Nuria Lopez-Bigas, Analia Azaro, Monica Arnedos, Javier Hernández-Losa, Maurizio Scaltriti, Mafalda Oliveira, Laia Monserrat, Marta Capelán, Maria Teresa Herrera-Abreu, Carlos Caldas, Guillermo Villacampa, Leonardo Mina, Judit Grueso, Chandra S. Verma, Srinivasaraghavan Kannan, Robert Clarke, Nusaibah Ibrahimi, R. Dienstmann, Andreu Ódena, Nicholas C. Turner, Fara Brasó-Maristany, Aleix Prat, Mònica Sánchez-Guixé, Kui Lin, Gonzalez-Perez, Abel [0000-0002-8582-4660], Oliveira, Mafalda [0000-0001-9152-8799], Ibrahimi, Nusaibah [0000-0003-4537-0323], Kannan, Srinivasaraghavan [0000-0002-9539-5249], Sánchez-Guixé, Mònica [0000-0002-9430-4413], Hernández, Javier [0000-0003-1526-3201], Clarke, Robert B [0000-0001-5407-3123], Caldas, Carlos [0000-0003-3547-1489], Arribas, Joaquín [0000-0002-0504-0664], Michiels, Stefan [0000-0002-6963-2968], Turner, Nicholas C [0000-0001-8937-0873], Prat, Aleix [0000-0003-2377-540X], Nuciforo, Paolo [0000-0003-1380-0990], Lopez-Bigas, Nuria [0000-0003-4925-8988], Scaltriti, Maurizio [0000-0002-5522-1447], Saura, Cristina [0000-0001-8296-5065], Serra, Violeta [0000-0001-6620-1065], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Palafox M, Monserrat L, Òdena A, Sánchez-Guixé M, Rodríguez O, Guzmán M, Grueso J] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Bellet M, Bellet M, Capelán M, Azaro A, Saura C] Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Villacampa G, Viaplana C, Dienstmann R] Oncology Data Science Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Gonzalez-Perez A] Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain. Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain. [Hernández J] Grup de Recerca de Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Arribas J] CIBERONC, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Growth Factors Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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endocrine system ,Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES] ,endocrine system diseases ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Ubiquitin-Protein Ligases ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,General Physics and Astronomy ,Antineoplastic Agents ,Breast Neoplasms ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Predictive markers ,Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS] ,General Biochemistry, Genetics and Molecular Biology ,Càncer de mama ,Phosphatidylinositol 3-Kinases ,Text mining ,Breast cancer ,Er breast cancer ,Medicine ,Humans ,Cancer models ,neoplasms ,Protein Kinase Inhibitors ,Resistència als medicaments ,fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS] ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Multidisciplinary ,Manchester Cancer Research Centre ,acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS] ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Inhibitor resistance ,Cyclin-Dependent Kinase 4 ,General Chemistry ,Cyclin-Dependent Kinase 6 ,Proteïnes quinases - Inhibidors ,Retinoblastoma Binding Proteins ,Receptors, Estrogen ,Drug Resistance, Neoplasm ,Drug resistance ,Mama - Càncer - Tractament ,Cancer research ,Female ,business ,Biomarkers - Abstract
CDK4/6 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. This study has been supported by the Susan G. Komen Foundation (CCR15330331) and by the Catalan Agency AGAUR (2017 SGR 540) [to V.S.]. V.S. received funds from the Instituto de Salud Carlos III: grants PI13/01714, CP14/00228, MV15/00041, CPII19/00033 and PI20/00892. M.P. received a Juan de la Cierva Grant from the Ministerio de Economía y Competitividad (FJCI-2015-25412), L.Mo. a grant from FI-AGAUR (2019 FI_B 01199), F.B-M. a grant from the Fundación Científica Asociación Española Contra el Cáncer (AECC_Postdoctoral17-1062) and M.S-G, a Marie Slodowska-Curie Innovative Training Networks PhD fellowship (H2020-MSCA-ITN-2015_675392). This work was supported by Breast Cancer Research Foundation (BCRF-19-08), Instituto de Salud Carlos III Project Reference number AC15/00062 and the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181) and Asociación Española Contra el Cáncer (to J.A.). R.B.C. laboratory is supported by Breast Cancer Now (grant numbers: MAN-Q1 and MAN-Q2), NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007) and EdiREX Horizon 2020 grant No.731105. The xenograft program in the C.C. laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). This work has been supported by NIH grants P30 CA008748 and RO1CA190642-01, the CDMRP grant BC171535P1, and the Breast Cancer Research Foundation [to M.S.]. A.P. received funds from Instituto de Salud Carlos III—PI16/00904 and PI19/01846, Breast Cancer Now—2018NOVPCC1294, Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-PRAT, Fundació La Marató TV3 201935-30, the European Union’s Horizon 2020 research and innovation program H2020-SC1-BHC-2018-2020. IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). C. S. Verma reports grants from MSD International and grants from Ipsen outside the submitted work.
- Published
- 2022
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