Breast and ovarian cancers rank among the top causes of cancer-related death in women. Despite effective endocrine and chemotherapy, resistance remains a challenge due to various cellular processes. Identifying targetable molecular biomarkers can enhance current therapies. Molecular characterization of gene expression in patients revealed successful targeted therapies. Genomic alterations in the PI3K/AKT pathway, crucial in cancer, make AKT a promising therapeutic target. Small molecule inhibitors targeting AKT may improve anticancer treatments.
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AKT Function and Structure
AKT, a serine-threonine kinase, regulates crucial biological functions like cell proliferation, survival, glucose metabolism, protein synthesis, genome stability, and apoptosis inhibition in response to diverse stimuli. Its activation is observed in various human cancers, contributing to tumor aggressiveness and drug resistance. There are three human AKT isoforms (AKT1, AKT2, AKT3) with shared structure and activation mechanisms. The N-terminal pleckstrin homology (PH) domain aids membrane recognition, while the central kinase domain requires threonine phosphorylation for activation. The C-terminal region contains a serine residue crucial for phosphorylation. Despite 80% homology, isoforms have specific functions. AKT1 in cell growth, AKT2 in energy/metabolism, and AKT3, less studied, implicated in brain development and glioma cell viability.
Fig. 1 Representation of AKT pathway and downstream effectors (Shariati M., Meric-Bernstam F. 2019).
AKT Activation Mechanism
AKT activation is initiated by ligands binding to cell membrane receptors, including growth factors like IGF-1 and PDGF. Downstream of the PI3K pathway, activated RTK leads to PI3K activation, recruiting AKT to the membrane. Phosphorylation by PDK1 and mTORC2 at Thr308 and Ser473 activates AKT. PTEN and PHLPP negatively regulate AKT through dephosphorylation. Activated AKT phosphorylates substrates involved in cancer, including mTOR, TSC1/2, p70S6K, 4E-BP1, PRAS40, and YAP, influence cell metabolism, protein synthesis, and cell cycle progression. AKT also regulates apoptosis by inhibiting BAD, BIM, caspase 9, and FoxO1, and promoting MDM2-mediated p53 degradation. These intricate processes highlight AKT's pivotal role in cellular functions and cancer development.
AKT Activation in Breast and Ovarian Cancers
AKT dysregulation is common in various cancers, including breast and ovarian. While AKT1 amplification is prevalent, an activating mutation (AKT1-E17K) is identified in breast, ovarian, and colorectal cancers, playing a crucial role in development. AKT2 overexpression is observed in ovarian and breast carcinomas, with amplification associated with poor prognosis in high-grade ovarian tumors. AKT2 overexpression enhances invasion and metastasis in breast and ovarian cancer cells. AKT3, the least studied isoform, shows upregulation in triple-negative breast cancer and exhibits a novel mutation in HER2-amplified breast cancer with trastuzumab resistance. Increased AKT3 expression is seen in ovarian tumors and primary melanomas, promoting G2/M transition in ovarian cancer cell lines. These findings emphasize the diverse roles of AKT isoforms in cancer initiation and progression.
AKT Inhibitors as Anticancer Treatments
The research field of AKT inhibitors as anticancer treatments is continuously expanding. Currently, various categories of AKT inhibitors have entered clinical trials, including ATP competitive and allosteric inhibitors. Among them, drugs such as Ipatasertib (GDC-0068), Capivasertib (AZD5363), ARQ751, and ARQ092 have demonstrated promising efficacy in inhibiting the AKT pathway. These inhibitors show potential therapeutic effects across multiple cancer types, particularly exhibiting significant clinical activity in the treatment of breast cancer and ovarian cancer. However, no AKT inhibitor has received clinical approval yet, and current research is still searching for more selective and effective drugs to maximize their potential therapeutic roles. With a deeper understanding of the mechanism of action of the AKT pathway, clinical trials designed based on mechanistic insights will better showcase the therapeutic potential of AKT inhibitors, providing a more comprehensive clinical perspective for future cancer treatments.
In conclusion, the comprehensive understanding of AKT's pivotal role in cancer progression has led to the development of numerous inhibitors. While first-generation inhibitors showed limited clinical efficacy, ongoing clinical trials focus on combinatorial approaches and patient stratification based on molecular alterations. Overcoming challenges related to isoform selectivity and off-target effects remains critical for the successful translation of AKT inhibitors into clinical practice. As research continues to unravel the complexities of the PI3K/AKT pathway, the promise of AKT inhibitors as effective anticancer therapies in breast and ovarian cancers remains a topic of keen interest and investigation.
References
- Shariati M., Meric-Bernstam F. Targeting AKT for cancer therapy. Expert Opinion on Investigational Drugs. 2019, 28(11): 977-988.
- Martini M., et al. PI3K/AKT signaling pathway and cancer: an updated review. Annals of Medicine. 2014, 46(6): 372-383.
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