High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
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. H...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/170848 |
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| author | Palafox, Marta Monserrat, Laia Bellet, Meritxell Villacampa, Guillermo Gonzalez-Perez, Abel Oliveira, Mafalda Brasó-Maristany, Fara Ibrahimi, Nusaibah Kannan, Srinivasaraghavan Mina, Leonardo Herrera-Abreu, Maria Teresa Òdena, Andreu Sánchez-Guixé, Mònica Capelán, Marta Azaro, Analía Bruna, Alejandra Rodríguez, Olga Guzmán, Marta Grueso, Judit Viaplana, Cristina Hernández, Javier Su, Faye Lin, Kui Clarke, Robert B. Caldas, Carlos Arribas, Joaquín Michiels, Stefan García-Sanz, Alicia Turner, Nicholas C. Prat, Aleix Nuciforo, Paolo Dienstmann, Rodrigo Verma, Chandra Shekhar Lopez-Bigas, Nuria Scaltriti, Maurizio Arnedos, Monica Saura, Cristina Serra, Violeta |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Palafox, Marta Monserrat, Laia Bellet, Meritxell Villacampa, Guillermo Gonzalez-Perez, Abel Oliveira, Mafalda Brasó-Maristany, Fara Ibrahimi, Nusaibah Kannan, Srinivasaraghavan Mina, Leonardo Herrera-Abreu, Maria Teresa Òdena, Andreu Sánchez-Guixé, Mònica Capelán, Marta Azaro, Analía Bruna, Alejandra Rodríguez, Olga Guzmán, Marta Grueso, Judit Viaplana, Cristina Hernández, Javier Su, Faye Lin, Kui Clarke, Robert B. Caldas, Carlos Arribas, Joaquín Michiels, Stefan García-Sanz, Alicia Turner, Nicholas C. Prat, Aleix Nuciforo, Paolo Dienstmann, Rodrigo Verma, Chandra Shekhar Lopez-Bigas, Nuria Scaltriti, Maurizio Arnedos, Monica Saura, Cristina Serra, Violeta |
| author_sort | Palafox, Marta |
| collection | NTU |
| description | 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. |
| first_indexed | 2025-02-19T03:47:11Z |
| format | Journal Article |
| id | ntu-10356/170848 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:47:11Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1708482023-10-09T15:32:18Z High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer Palafox, Marta Monserrat, Laia Bellet, Meritxell Villacampa, Guillermo Gonzalez-Perez, Abel Oliveira, Mafalda Brasó-Maristany, Fara Ibrahimi, Nusaibah Kannan, Srinivasaraghavan Mina, Leonardo Herrera-Abreu, Maria Teresa Òdena, Andreu Sánchez-Guixé, Mònica Capelán, Marta Azaro, Analía Bruna, Alejandra Rodríguez, Olga Guzmán, Marta Grueso, Judit Viaplana, Cristina Hernández, Javier Su, Faye Lin, Kui Clarke, Robert B. Caldas, Carlos Arribas, Joaquín Michiels, Stefan García-Sanz, Alicia Turner, Nicholas C. Prat, Aleix Nuciforo, Paolo Dienstmann, Rodrigo Verma, Chandra Shekhar Lopez-Bigas, Nuria Scaltriti, Maurizio Arnedos, Monica Saura, Cristina Serra, Violeta School of Biological Sciences Bioinformatics Institute, A*STAR Science::Biological sciences Abemaciclib Advanced Breast Cancer 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. Published version The ABC-POP received funding from the Breast Cancer Research Foundation and research grants from Pfizer and Eli-Lilly, respectively (to M.A.). 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 cofinanced 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-BRC1215-20007) 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. 2023-10-08T07:57:10Z 2023-10-08T07:57:10Z 2022 Journal Article Palafox, M., Monserrat, L., Bellet, M., Villacampa, G., Gonzalez-Perez, A., Oliveira, M., Brasó-Maristany, F., Ibrahimi, N., Kannan, S., Mina, L., Herrera-Abreu, M. T., Òdena, A., Sánchez-Guixé, M., Capelán, M., Azaro, A., Bruna, A., Rodríguez, O., Guzmán, M., Grueso, J., ...Serra, V. (2022). High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer. Nature Communications, 13(1), 5258-. https://dx.doi.org/10.1038/s41467-022-32828-6 2041-1723 https://hdl.handle.net/10356/170848 10.1038/s41467-022-32828-6 36071033 2-s2.0-85137416617 1 13 5258 en Nature Communications © 2022 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |
| spellingShingle | Science::Biological sciences Abemaciclib Advanced Breast Cancer Palafox, Marta Monserrat, Laia Bellet, Meritxell Villacampa, Guillermo Gonzalez-Perez, Abel Oliveira, Mafalda Brasó-Maristany, Fara Ibrahimi, Nusaibah Kannan, Srinivasaraghavan Mina, Leonardo Herrera-Abreu, Maria Teresa Òdena, Andreu Sánchez-Guixé, Mònica Capelán, Marta Azaro, Analía Bruna, Alejandra Rodríguez, Olga Guzmán, Marta Grueso, Judit Viaplana, Cristina Hernández, Javier Su, Faye Lin, Kui Clarke, Robert B. Caldas, Carlos Arribas, Joaquín Michiels, Stefan García-Sanz, Alicia Turner, Nicholas C. Prat, Aleix Nuciforo, Paolo Dienstmann, Rodrigo Verma, Chandra Shekhar Lopez-Bigas, Nuria Scaltriti, Maurizio Arnedos, Monica Saura, Cristina Serra, Violeta High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer |
| title | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer |
| title_full | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer |
| title_fullStr | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer |
| title_full_unstemmed | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer |
| title_short | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer |
| title_sort | high p16 expression and heterozygous rb1 loss are biomarkers for cdk4 6 inhibitor resistance in er breast cancer |
| topic | Science::Biological sciences Abemaciclib Advanced Breast Cancer |
| url | https://hdl.handle.net/10356/170848 |
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