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

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.

Highlights

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer
We assessed the efficacy of the AKT inhibitor (AKTi) capivasertib, CDK4/6i palbociclib, and the ER degrader fulvestrant as single agents and in double and triple combinations in estrogen receptor-positive (ER+)MCF-7, T47D, and ZR-75-1 fulvestrant-resistant and fulvestrant-sensitive breast cancer cell models
We observed that the triple combination suppressed the growth of 182R-1 cells up to 8 weeks and T47D-derived fulvestrant-resistant cell lines (T47D R) over the entire 12 weeks of treatment (Fig. 1N and P), while relatively rapid outgrowth was observed with combined fulvestrant and CDK4/6i or AKTi (1 week for 182R-1 and 3–5 weeks for T47D R)

Summary

Introduction

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. 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. Clinical studies have demonstrated that combined CDK4/6i and endocrine therapy significantly improves progression-free survival (PFS) and overall survival (OS) compared to endocrine therapy alone in ER+ advanced breast cancer, resulting in the approval of CDK4/6i in the first-line setting combined with an aromatase inhibitor (AI). There are several AKT inhibitors (AKTi) under clinical investigation, including the pan-AKT kinase catalytic inhibitor capivasertib (AZD5363) that, in combination with fulvestrant, has recently been demonstrated to improve PFS in ER+ metastatic breast cancer patients whose tumors progressed on an AI19

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