The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

Abstract

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…Dysfunction of this pathway is related to not only the occurrence and development of tumours but also many other human diseases, such as leukaemia, diabetes, and schizophrenia [9][10][11]. Researchers have gradually gained a strong understanding of PI3K/AKT/mTOR signalling pathway regulation and function and agree that thoroughly elucidating the mechanism of PI3K/AKT/mTOR signal transmission and the related upstream and downstream molecules is necessary [12][13][14]. Such knowledge will help facilitate the use of this pathway as a target for treating tumours and other related diseases.…”

Endocrine-Resistant Breast Cancer: Mechanisms and Treatment

“…Receptor tyrosine kinases (RTKs) are a family of cell membrane-bound receptors whose intracellular do- main contains a tyrosine kinase that phosphorylates tyrosine residues of target proteins [20]. RTKs (e.g., epidermal growth factor receptor [EGFR/ErbB family], insulin-like growth factor receptors [IGFR], vascular endothelial growth factor receptors [VEGFR], and fibroblast growth factor receptors [FGFR]) are activated upon ligand binding, which are mainly growth factors, cytokines, or hormones, and their activation/overexpression is associated with endocrine resistance [21][22][23][24].…”

Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives

“…Chemotherapy, radiotherapy, and prostatectomy are strategies in PC therapy, but recurrence and resistance of PC cells are problems, requiring novel strategies in PC therapy [ 138 , 139 ]. Increasing evidence demonstrates that PI3K/Akt and MAPK signaling pathways account for an increase in proliferation and metastasis of cancer cells, and their inhibition is important in cancer therapy [ 140 , 141 , 142 , 143 ]. In PC cells, chrysin down-regulates the expression of the PI3K/Akt pathway to interrupt the proliferation of PC cells.…”