Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic

Abstract

The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.

Inhibition of Vps34 and p110δ PI3K Impairs Migration, Invasion and Three-Dimensional Spheroid Growth in Breast Cancer Cells

“…The PI3K/Akt/mTOR pathway is turned off by phosphatase and tensin homologue deleted on chromosome ten (PTEN) by dephosphorylating phosphatidylinositol-3,4,5-triphosphate (PIP3) into phosphatidylinositol-4,5-triphosphate (PIP2) [ 26 ]. The mechanism of PI3K/Akt/mTOR resistance may occur at different levels in BC [ 30 , 31 , 33 , 34 , 35 ]. First, upregulation of receptor tyrosine kinase (RTK) may enhance activation of the PI3K/Akt/mTOR pathway [ 30 ].…”

“…First, upregulation of receptor tyrosine kinase (RTK) may enhance activation of the PI3K/Akt/mTOR pathway [ 30 ]. In addition, mutations in the PIK3CA gene leading to hyperactivation of the p110α PI3K catalytic subunit have been reported to occur in 30–40% of patients with ER+ BC and in 20–25% of BC patients with overexpression of ERB2, and mutations in Akt1 and PTEN have been found in 13–24% and 7% of ER+ BC patients, respectively [ 31 , 33 , 35 ]. In addition, PI3K/Akt can phosphorylate ERa at S167 in the activation function 1 domain (AF1) in the absence of estrogen, and mitogen-activated protein kinase (MAPK) at S118 in AF1, leading to estrogen-independent ER activation [ 30 , 31 , 35 ].…”

“…In addition, mutations in the PIK3CA gene leading to hyperactivation of the p110α PI3K catalytic subunit have been reported to occur in 30–40% of patients with ER+ BC and in 20–25% of BC patients with overexpression of ERB2, and mutations in Akt1 and PTEN have been found in 13–24% and 7% of ER+ BC patients, respectively [ 31 , 33 , 35 ]. In addition, PI3K/Akt can phosphorylate ERa at S167 in the activation function 1 domain (AF1) in the absence of estrogen, and mitogen-activated protein kinase (MAPK) at S118 in AF1, leading to estrogen-independent ER activation [ 30 , 31 , 35 ]. Moreover, PI3K/Akt promotes chemotherapy-resistant proteins such as Multidrug Resistance Associated Protein 1 (MRP1), ABCG2, P-glycoprotein, and anti-apoptotic effects [ 30 ].…”

“…Moreover, PI3K/Akt promotes chemotherapy-resistant proteins such as Multidrug Resistance Associated Protein 1 (MRP1), ABCG2, P-glycoprotein, and anti-apoptotic effects [ 30 ]. Furthermore, preclinical studies suggest that inhibition of the PI3K/Akt/mTOR pathway can restore sensitivity to endocrine therapy, anti-HER2 therapy, and chemotherapy [ 30 , 31 , 33 , 34 , 35 ]. Therefore, it is critical to find novel therapeutic strategies that can interfere with the molecular mechanisms that drive proliferation and metastasis.…”

Overexpression of COL11A1 confers tamoxifen resistance in breast cancer

“…On the other hand, activation of receptor tyrosine kinases has been observed in endocrine resistant tumors and been reported to induce tamoxifen resistance 6 – 9 . In addition, cross-talk between alternative signaling pathways involving cell proliferation and survival has also been demonstrated to promote tamoxifen resistance 10 – 12 . In view of the complexity of mechanisms underlie resistance, it is imperative to identify potential molecular markers associated with therapeutic response.…”