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Review
. 2021 Mar 15:12:628690.
doi: 10.3389/fphar.2021.628690. eCollection 2021.

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

Chao Dong  1 , Jiao Wu  1 , Yin Chen  2 , Jianyun Nie  3 , Ceshi Chen  4   5
Affiliations
Review

Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

Chao Dong et al. Front Pharmacol. .

Abstract

Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer VSports手机版. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer. .

Keywords: PI3K; chemotherapy; drug resistance; endocrine therapy; targeted therapy. V体育安卓版.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
PI3K/AKT signaling pathway in breast cancer. EGF(R): epidermal growth factor (receptor); PI3K: phosphatidylinositol 3-kinase; PDK1/2: 3-phosphoinositide dependent kinase-1/2; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa-B; MMP9: matrix metallo protein 9; VEGF: vascular endothelial growth factor.
FIGURE 2
FIGURE 2
PI3K/AKT pathway and hormone therapy resistance. The interaction between ER signaling and the RTK pathway is considered a major mechanism of resistance to hormone therapy. Upregulation of both the PI3K/AKT/mTOR and RAS/RAF/MAPK pathways activates the ERα-independent pathway in the absence of estrogen though extranuclear ER signaling, thus causing estrogen-regulated gene activation that ultimately promotes cancer cell survival and leads to hormone therapy resistance.
FIGURE 3
FIGURE 3
PI3K/AKT pathway and HER2-targeted therapy resistance. High expression of the HER2 truncated mutant (p95-HER2), the most common form of HER2 structural change, is related to HER2-targeted therapy resistance through activating the PI3K/AKT pathway. Trastuzumab treatment increases HER3 expression and leads to PI3K/AKT activation along with subsequent resistance to anti-HER2 therapy. Additionally, PI3KCA mutations, PTEN loss or both, also contribute to PI3K activation and then promote cell proliferation along with resistance to HER2-targeted therapy.
FIGURE 4
FIGURE 4
PI3K/AKT pathway is related to chemotherapy, CDK4/6 and PARP inhibitor resistance. 1) ABC transporters, including BCRP and P-gp, enhance the efflux of chemotherapeutic drugs and cause chemoresistance. PI3K/AKT promotes BCRP transcription via the KEAP1-Nrf2 axis and NF-κB pathway and induces P-gp expression with an uncharacterized mechanism. Subsequently, drug outflow is increased through ABC transporters, which ultimately results in resistance to chemotherapy in breast cancer. ABC: ATP-binding cassette; KEAP1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factorerythroid-derived 2. 2) The CDK4/6 complex promotes Rb phosphorylation and dissociates Rb from E2F transcription factors, thus promoting cell cycle G1-S phase progression and cell survival. CDK4/CDK6 inhibitors can block this process and inhibit tumor cell proliferation. However, CDK4/CDK6 inhibition therapy leads to PI3K/AKT pathway activation via phosphorylation of AKT at the S477/T479 site by PDK1. Additionally, activated AKT can also upregulate cyclin D expression by inhibiting GSK3 phosphorylation. As a result, breast cancer cells gradually become resistant to CDK4/CDK6 inhibitors. CDK4/CDK6: Cyclin D/cyclin-dependent kinase 4/6; Rb: retinoblastoma protein. 3) PARP is activated by DNA damage and catalyzes the covalent coupling of branched chains of ADP-ribose units, thus promoting DNA repair and maintaining genomic stability. In BRCA-mutated cells, double-strand broken DNA is unable to be repaired via homologous recombination; such cells fail to repair and ultimately exhibit synthetic lethality in the presence of DNA damage and PARP inhibitors. Suppression of PARP1 activity induces AKT and its downstream target GSK3β phosphorylation via Src and facilitates cytoplasmic translocation of the pATM-NEMO complex and thereby forms a cytoprotective signalosome, both of which contribute to mitochondrial protection under oxidative stress conditions and lead to acquired resistance to PARP inhibitors. PARP: Poly (ADP-ribose) polymerases; SSB: Single-strand break; DSB: Double-strand break.
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