Academic Journal
High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.
| العنوان: | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer. |
|---|---|
| المؤلفون: | Palafox, M, Monserrat, L, Bellet, M, Villacampa, G, Gonzalez-Perez, A, Oliveira, M, Brasó-Maristany, F, Ibrahimi, N, Kannan, S, Mina, L, Herrera-Abreu, MT, Òdena, A, Sánchez-Guixé, M, Capelán, M, Azaro, A, Bruna, A, Rodríguez, O, Guzmán, M, Grueso, J, Viaplana, C, Hernández, J, Su, F, Lin, K, Clarke, RB, Caldas, C, Arribas, J, Michiels, S, García-Sanz, A, Turner, NC, Prat, A, Nuciforo, P, Dienstmann, R, Verma, CS, Lopez-Bigas, N, Scaltriti, M, Arnedos, M, Saura, C, Serra, V |
| المساهمون: | Bruna Cabot, Alejandra, Turner, Nicholas |
| بيانات النشر: | NATURE PORTFOLIO |
| سنة النشر: | 2022 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| مصطلحات موضوعية: | Antineoplastic Agents, Biomarkers, Breast Neoplasms, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Female, Humans, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Receptors, Estrogen, Retinoblastoma Binding Proteins, Ubiquitin-Protein Ligases |
| جغرافية الموضوع: | England |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Electronic; application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| Relation: | ARTN 5258; Nature Communications, 2022, 13 (1), pp. 5258 -; https://repository.icr.ac.uk/handle/internal/5606 |
| DOI: | 10.1038/s41467-022-32828-6 |
| الاتاحة: | https://doi.org/10.1038/s41467-022-32828-6 https://repository.icr.ac.uk/handle/internal/5606 |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.D6C817B8 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
|---|---|
| DOI: | 10.1038/s41467-022-32828-6 |