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Review
. 2021 Apr 14;4(3):573-595.
doi: 10.20517/cdr.2021.05. eCollection 2021.

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Affiliations
Review

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Natasha Rinne et al. Cancer Drug Resist. .

Abstract

The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials.

Keywords: Ovarian cancer; PI3K/AKT/mTOR pathway; chemotherapy resistance; high-grade serous; inhibitors; therapeutics.

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Conflict of interest statement

All authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Overview of PI3K/AKT/mTOR signaling pathway. Activation (blue arrows) of growth factor (GF) receptor tyrosine kinase (RTK), resulting in autophosphorylation on tyrosine residues, recruits Phosphatidyl-inositol-3-kinase (PI3K) to the cell membrane. Direct binding of PI3K to the tyrosine residues causes activation via the PI3K catalytic subunit[42]. Activated PI3K in turn phosphorylates secondary messenger phosphatidylinositol-3,4,5-bisphospate (PIP2) which converts to phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 is responsible for the recruitment of the protein kinase AKT to the cell surface where its subsequent activation/inhibition by multiple molecules leads to involvement in numerous downstream signaling pathways[43,44]. AKT is activated via phosphorylation at two key residues: S473 and T308[40]. Protein serine/threonine kinase-3’-PDK1 and PDK2, recruited to and activated at the cell surface are responsible for activating AKT, along with protein kinases ATM and ATR, and HSP90. DNA-PK, a nuclear serine/threonine kinase essential for non-homologous end-joining (NHEJ) repair, activates AKT via phosphorylation at S473 in response to cisplatin-induced DNA damage in platinum resistant EOC cells[19]. PTEN, tuberous sclerosis protein 1 (TSC1) and TSC2 are the main negative regulators (yellow arrows) of the pathway, with phosphorylation of TSC2 by AKT releasing the inhibitory effect on mTORC1 via the GTP-binding protein Rheb[42]. mTORC1 activates p70S6K and inhibits 4E-BP1, resulting in protein synthesis and cell growth, and mTORC2 activates AKT itself; overall mTOR activation leads to cell growth and survival. Inactivation of pro-apoptotic molecules YAP, Procaspase 9 (Casp9) and BAD, as well as inhibiting Forkhead transcription factors [e.g., Forkhead box protein O1 (FoxO1)] result in increased cell survival[45,46]. AKT is an essential part of the insulin signaling pathway. Activated in response to insulin stimulation, AKT causes Glucose Transporter 4 (GLUT4) to translocate to the cell surface, facilitating glucose uptake. Additionally, the inhibition of glycogen synthase kinase 3 beta (GSK-3β) by AKT increases glycogen production[47]. The role of AKT in glucose metabolism is again apparent through its inhibition of FoxO1, which suppresses hepatic glucose production[48]. The PI3K/AKT/mTOR signaling pathway includes points of cross-regulation and communication with other common signaling pathways, e.g., JNK and RAS-ERK. The AKT substrate c-RAF is activated by RAS and initiates a kinase cascade leading to ERK activation[49]. The phosphorylation of c-RAF by AKT inhibits its activity and subsequent downstream activity in the RAS/RAF/MEK/ERK signaling cascade known for its role in apoptosis and cell differentiation[50]. AKT involvement with the JNK pathway, a stress- and nutrient-response pathway, directly modifies activation of target genes, many of which are involved in adaptations to extra-cellular stresses[51].

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