Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer

Carla L. Alves*, Sidse Ehmsen, Mikkel G. Terp, Neil Portman, Martina Tuttolomondo, Odd L. Gammelgaard, Monique F. Hundebøl, Kamila Kaminska, Lene E. Johansen, Martin Bak, Gabriella Honeth, Ana Bosch, Elgene Lim, Henrik J. Ditzel

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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.

Original languageEnglish
Article number5112
JournalNature Communications
Number of pages15
Publication statusPublished - 25. Aug 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).


  • Breast Neoplasms/drug therapy
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4/antagonists & inhibitors
  • Cyclin-Dependent Kinase 6/antagonists & inhibitors
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Drug Therapy, Combination
  • Female
  • Fulvestrant/administration & dosage
  • Humans
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors/administration & dosage
  • Proto-Oncogene Proteins c-akt/genetics


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