Abstract
The AKT protein kinase plays a central role in several interconnected molecular pathways involved in growth, apoptosis, angiogenesis, and cell metabolism. It thereby represents a therapeutic target, especially in hormone receptor-positive (HR) breast cancers, where the PI3K/AKT signaling pathway is largely hyperactivated. Moreover, resistance to therapeutic classes, including endocrine therapy, is associated with the constitutive activation of the PI3K/AKT pathway. Improved knowledge on the molecular mechanisms underlying resistance to endocrine therapy has led to the diversification of the therapeutic arsenal, notably with the development of PI3K and mTOR inhibitors, which are currently approved for the treatment of advanced HR-positive breast cancer patients. AKT itself constitutes a novel pharmacological target for which AKT inhibitors have been developed and tested in clinical trials. However, despite its pivotal role in cell survival and anti-apoptotic mechanisms, as well as in endocrine therapy resistance, few drugs have been developed and are available for clinical practice. The scope of the present review is to focus on the pivotal role of AKT in metastatic breast cancer through the analysis of its molecular features and to discuss clinical implications and remaining challenges in the treatment of HR-positive metastatic breast cancer.
Highlights
Breast cancer is the leading cause of cancer-related deaths in women worldwide
The scope of the present review is to focus on the pivotal role of AKT in estrogen-receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer from a molecular point of view; we will subsequently present the molecular features of the AKT pathway and its involvement in endocrine therapy resistance before discussing current and perspective treatments in clinical practice through the promises and pitfalls encountered in clinical practice
Among more advanced trials involving AKT inhibitors, the FAKTION phase II study evaluated whether the addition of capivasertib to fulvestrant improved progression-free survival (PFS) in patients with advanced breast cancer in the context of endocrine resistance
Summary
Breast cancer is the leading cause of cancer-related deaths in women worldwide. Though longer life spans and decreased rates of breast cancer-specific mortality have been achieved for localized stage tumors thanks to advances in population screening and earlystage treatments, metastatic breast cancer remains an incurable disease. The SOLAR-1 trial evaluated a PI3Kα-specific inhibitor, alpelisib, and reported a prolonged PFS among patients harboring PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancers who had previously received endocrine therapy [12]. Another phase III trial involving buparlisib, a pan-PI3K inhibitor targeting all four isoforms of class I PI3K (α, β, γ, δ) in combination with endocrine therapy (fulvestrant), was published, presenting data on the efficacy of the inhibitor on patients with PIK3CA mutations. The scope of the present review is to focus on the pivotal role of AKT in estrogen-receptor-positive, HER2-negative metastatic breast cancer from a molecular point of view; we will subsequently present the molecular features of the AKT pathway and its involvement in endocrine therapy resistance before discussing current and perspective treatments in clinical practice through the promises and pitfalls encountered in clinical practice
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