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 and Henrik J. Ditzel ()
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Carla L. Alves: University of Southern Denmark
Sidse Ehmsen: University of Southern Denmark
Mikkel G. Terp: University of Southern Denmark
Neil Portman: Garvan Institute of Medical Research
Martina Tuttolomondo: University of Southern Denmark
Odd L. Gammelgaard: University of Southern Denmark
Monique F. Hundebøl: University of Southern Denmark
Kamila Kaminska: Lund University
Lene E. Johansen: University of Southern Denmark
Martin Bak: Department of Pathology, Sydvestjysk Sygehus
Gabriella Honeth: Lund University
Ana Bosch: Lund University
Elgene Lim: Garvan Institute of Medical Research
Henrik J. Ditzel: University of Southern Denmark

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25422-9

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