2. Academic Validation
  3. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer

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

  • Nat Commun. 2021 Aug 25;12(1):5112. doi: 10.1038/s41467-021-25422-9.
Carla L Alves 1,  Sidse Ehmsen  # 2 3,  Mikkel G Terp  # 2,  Neil Portman 4 5,  Martina Tuttolomondo 2,  Odd L Gammelgaard 2,  Monique F Hundebøl 2,  Kamila Kaminska 6,  Lene E Johansen 2,  Martin Bak 7,  Gabriella Honeth 6,  Ana Bosch 6,  Elgene Lim 4 5,  Henrik J Ditzel 8 9 10
Affiliations

Affiliations

  • 1 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. calves@health.sdu.dk.
  • 2 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 3 Department of Oncology, Institute of Clinical Research, Odense University Hospital, Odense, Denmark.
  • 4 Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • 5 St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW, Australia.
  • 6 Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 7 Department of Pathology, Sydvestjysk Sygehus, Esbjerg, Denmark.
  • 8 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. hditzel@health.sdu.dk.
  • 9 Department of Oncology, Institute of Clinical Research, Odense University Hospital, Odense, Denmark. hditzel@health.sdu.dk.
  • 10 Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense, Denmark. hditzel@health.sdu.dk.
  • # Contributed equally.
PMID: 34433817 DOI: 10.1038/s41467-021-25422-9
Abstract

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.

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