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.
Bibliografisk noteFunding Information:
We would like to thank Anne E. Lykkesfeldt for providing MCF-7 and T47D fulvestrant-resistant cell line models, Lisbet Mortensen and Ole Nielsen at the Department of Pathology, Odense University Hospital, for excellent technical assistance with the immunohistochemistry, and M. Kat Occhipinti for editorial assistance. This study was supported by grants from the Danish Cancer Society, A Race Against Breast Cancer, Region of Southern Denmark Research Foundation, and Odense University Hospital Research Council to H.J.D. E.L. is supported by a National Breast Cancer Foundation endowed chair and Love Your Sister.