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

• Published in: Nature communications 2021-08, Vol.12 (1), p.5112-5112, Article 5112
• Main Authors: Alves, Carla L., Ehmsen, Sidse, Terp, Mikkel G., Portman, Neil, Tuttolomondo, Martina, Gammelgaard, Odd L., Hundebøl, Monique F., Kaminska, Kamila, Johansen, Lene E., Bak, Martin, Honeth, Gabriella, Bosch, Ana, Lim, Elgene, Ditzel, Henrik J.
• Format: Article
• Language: English
• Subjects: 13; 13/2; 13/51; 59; 64; 64/60; 692/308/575; 692/4028/67/1347; 96; 96/1; AKT protein; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Cancer and Oncology; Cancer och onkologi; Cell Line, Tumor; Clinical Medicine; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - genetics; Cyclin-Dependent Kinase 6 - metabolism; Disease Progression; Drug Resistance, Neoplasm; Drug Therapy, Combination; Endocrine therapy; Estrogen receptors; Estrogens; Female; Fulvestrant; Fulvestrant - administration & dosage; Humanities and Social Sciences; Humans; Inhibitors; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Metastases; Metastasis; Molecular Targeted Therapy; multidisciplinary; Patients; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); Therapy; Tumors; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25422-9

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.