Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer
| Autor: | Ana Bosch, Mikkel G. Terp, Henrik J. Ditzel, Monique F. Hundebøl, Neil Portman, Lene E. Johansen, Kamila Kaminska, Gabriella Honeth, Carla Maria Lourenco Alves, Martin Bak, Odd L. Gammelgaard, Elgene Lim, Martina Tuttolomondo, Sidse Ehmsen |
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| Rok vydání: | 2020 |
| Předmět: |
Fulvestrant/administration & dosage
endocrine system diseases medicine.drug_class Science General Physics and Astronomy Breast Neoplasms Proto-Oncogene Proteins c-akt/genetics Article General Biochemistry Genetics and Molecular Biology Metastasis Breast cancer Breast Neoplasms/drug therapy Cell Line Tumor Medicine Humans Molecular Targeted Therapy neoplasms Protein kinase B Fulvestrant Protein Kinase Inhibitors Multidisciplinary integumentary system business.industry Protein Kinase Inhibitors/administration & dosage Endocrine therapy Cancer Cyclin-Dependent Kinase 4 General Chemistry Cyclin-Dependent Kinase 6 Cyclin-Dependent Kinase 6/antagonists & inhibitors Translational research medicine.disease Publisher Correction Cyclin-Dependent Kinase 4/antagonists & inhibitors Estrogen Tumor progression Drug Resistance Neoplasm Cancer research Disease Progression Drug Therapy Combination Female biological phenomena cell phenomena and immunity business Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | Nature Communications Alves, C L, Ehmsen, S, Terp, M G, Portman, N, Tuttolomondo, M, Gammelgaard, O L, Hundebøl, M F, Kaminska, K, Johansen, L E, Bak, M, Honeth, G, Bosch, A, Lim, E & Ditzel, H J 2021, ' Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer ', Nature Communications, vol. 12, 5112 . https://doi.org/10.1038/s41467-021-25422-9 Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-25422-9 |
| Popis: | CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome. CDK4/6 inhibitors in combination with endocrine therapy has shown efficacy in ER + breast cancer patients but resistance can occur. Here, the authors demonstrate that co-targeting CDK4/6 and AKT with endocrine therapy prevents acquired resistance and therapy adaptation. |
| Databáze: | OpenAIRE |
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