In CDK4/6 Inhibitor and Endocrine Therapy–Resistant Breast Cancer, Co-Targeting CDK4/6 and AKT with Endocrine Therapy Prevents Progression

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In estrogen receptor–positive advanced breast cancer patients, cyclin-dependent kinase (CDK)4/6 inhibitors combined with endocrine therapy have shown impressive efficacy. Disease progression eventually occurs in most patients receiving this combination, highlighting the need for effective subsequent treatments or better initial therapies.

Alves and colleagues demonstrated that triple inhibition with fulvestrant, CDK4/6 inhibitor, and AKT inhibitor inhibits progression, durably weakens breast cancer cell growth, and decreases metastasis of tumor xenografts resistant to a CDK4/6 inhibitor-fulvestrant combination or fulvestrant alone.

Upon resistance to dual combination with AKT inhibitor and fulvestrant, switching from combined fulvestrant and CDK4/6 inhibitor does not prevent tumor progression.

Furthermore, growth of patient-derived xenografts resistant to combined CDK4/6 inhibitor and fulvestrant is significantly inhibited with triple combination with AKT inhibitor.

In metastasis of breast cancer patients treated with a combination of CDK4/6 inhibitor and endocrine therapy, high phospho-AKT levels are associated with shorter progression-free survival. This investigation suggests the potential of clinical development of estrogen receptor, CDK4/6, and AKT co-targeting strategies subsequent to progression on CDK4/6 inhibitor and endocrine therapy combination, and in tumors showing high phospho-AKT levels, which are linked with worse clinical outcomes.


Alves CL, Ehmsen S, Terp MG, et al. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer [published correction appears in Nat Commun. 2021 Sep 16;12:5588]. Nat Commun. 2021;12:5112.

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