Recent Advance of Akt Inhibitors in Clinical Trials

Guo, Kaiwen; Tang, Wendi; Zhuo, Huijun; Zhao, Guisen

doi:10.1002/slct.201901293

Cited by 16 publications

(12 citation statements)

References 34 publications

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“…Importantly, our study is the first to show that treatment with 50 µg/mL RE significantly inhibited phosphorylation/activation of Akt (Figure 3) in MDA-MB-231 cells. The recognition of enhanced Akt signaling in cancer, including breast cancer [87], has led to the development of novel agents targeting Akt, such as perifosine, BAY1125976, MK-2206, afuresertib, miransertib, and ipatasertib, all currently in clinical trials [88]. Some of these Akt-targeting agents are classified as allosteric inhibitors (MK-2206) while others (ipatasertib) are ATP-competitive inhibitors [89].…”

Section: Discussionmentioning

confidence: 99%

Rosemary Extract Inhibits Proliferation, Survival, Akt, and mTOR Signaling in Triple-Negative Breast Cancer Cells

Jaglanian

Tsiani

2020

IJMS

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Breast cancer is the most commonly diagnosed cancer in women. Triple-negative (TN) breast cancer lacks expression of estrogen receptor (ER), progesterone receptor (PR) as well as the expression and/or gene amplification of human epidermal growth factor receptor 2 (HER2). TN breast cancer is aggressive and does not respond to hormone therapy, therefore new treatments are urgently needed. Plant-derived chemicals have contributed to the establishment of chemotherapy agents. In previous studies, rosemary extract (RE) has been found to reduce cell proliferation and increase apoptosis in some cancer cell lines. However, there are very few studies examining the effects of RE in TN breast cancer. In the present study, we examined the effects of RE on TN MDA-MB-231 breast cancer cell proliferation, survival/apoptosis, Akt, and mTOR signaling. RE inhibited MDA-MB-231 cell proliferation and survival in a dose-dependent manner. Furthermore, RE inhibited the phosphorylation/activation of Akt and mTOR and enhanced the cleavage of PARP, a marker of apoptosis. Our findings indicate that RE has potent anticancer properties against TN breast cancer and modulates key signaling molecules involved in cell proliferation and survival.

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Section: Discussionmentioning

confidence: 99%

Rosemary Extract Inhibits Proliferation, Survival, Akt, and mTOR Signaling in Triple-Negative Breast Cancer Cells

Jaglanian

Tsiani

2020

IJMS

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“…Disruption of glycogen metabolism is also achieved by targeting mediators of glycogen biosynthesis including the PI3K/AKT/mTOR pathway. Modulators of this pathway, such as perifosine, MK-2202, and evorolimus, have progressed into clinical trials, however, it is not yet clear whether anticancer effects are mediated by impacts on tumor glycogen metabolism (103,104). Hyperactivation of the pathway is a prominent molecular feature of both clear cell ovarian and renal cell carcinomas (37,42,43,105).…”

Section: Pharmacological Disruption Of Glycogen Metabolism In Cancermentioning

confidence: 99%

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

et al. 2020

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Once thought to be exclusively a storage hub for glucose, glycogen is now known to be essential in a range of physiological processes and pathological conditions. Glycogen lies at the nexus of diverse processes that promote malignancy, including proliferation, migration, invasion, and chemoresistance of cancer cells. It is also implicated in processes associated with the tumor microenvironment such as immune cell effector function and crosstalk with cancer-associated fibroblasts to promote metastasis. The enzymes of glycogen metabolism are dysregulated in a wide variety of malignancies, including cancers of the kidney, ovary, lung, bladder, liver, blood, and breast. Understanding and targeting glycogen metabolism in cancer presents a promising but under-explored therapeutic avenue. In this review, we summarize the current literature on the role of glycogen in cancer progression and discuss its potential as a therapeutic target for cancer treatment.

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“…To date, several allosteric and ATP-competitive AKT inhibitors have been synthetized and tested in clinical trials ( Landel et al, 2020 ; Guo et al, 2019 ) ( Figure 2B ; Table 1 ). Allosteric inhibitors (ARQ092/miransertib; BAY1125976; MK-2206, TAS-117) were employed in advanced solid tumors in many early phase trials, but only MK-2206 has been further investigated in different BC subtypes ( Biondo et al, 2011 ; Doi et al, 2015 ; Hyman et al, 2018 ; Schneeweiss et al, 2019 ; Yunokawa et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

et al. 2021

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The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

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Recent Advance of Akt Inhibitors in Clinical Trials

Cited by 16 publications

References 34 publications

Rosemary Extract Inhibits Proliferation, Survival, Akt, and mTOR Signaling in Triple-Negative Breast Cancer Cells

Rosemary Extract Inhibits Proliferation, Survival, Akt, and mTOR Signaling in Triple-Negative Breast Cancer Cells

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

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