AKT as a Therapeutic Target for Cancer

Song, Mijung; Bode, Ann M.; Dong, Zigang; Lee, Mee-Hyun

doi:10.1158/0008-5472.can-18-2738

Cited by 583 publications

(471 citation statements)

References 106 publications

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“…AMPK is expressed ubiquitously and is involved in cell growth, metabolism and transcription, and plays a key role in the regulation of cellular and whole-body energy homeostasis [36][37][38]. The outputs of AKT signaling have been well reviewed [17,[39][40][41].…”

Section: Introductionmentioning

confidence: 99%

In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

et al. 2020

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The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. The deregulation of CAMKK2 is linked to several diseases, suggesting the utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work, we demonstrate that STO-609, frequently described as a selective inhibitor for CAMKK2, potently inhibits a significant number of other kinases. Through an analysis of literature and public databases, we have identified other potent CAMKK2 inhibitors and verified their activities in differential scanning fluorimetry and enzyme inhibition assays. These inhibitors are potential starting points for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.

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Section: Introductionmentioning

confidence: 99%

In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

et al. 2020

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“…The PI3K/AKT pathway is one of the most frequently activated signaling pathways in human cancers (134,135). AKT abnormal overexpression or activation has been reported in many human solid tumors and hematological malignancies, being associated with increased cancer cell proliferation and survival and becoming an important cancer therapeutic target (136,137). Receptor tyrosine kinases, such as IGF-1R, EGFR, human epidermal growth factor receptor 2 (HER2/ErbB2) and platelet-derived growth factor receptor (PDGFR), are activated in many cancers, and they trigger downstream signal cascades, including RAS/RAF/MAPK and PI3K/AKT signaling pathways (138)(139)(140)(141).…”

Section: Insulin-like Growth Factor (Igf) Systemmentioning

confidence: 99%

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

Mollinedo

Gajate

2020

Journal of Lipid Research

174

206

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Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.

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“…The phosphatidylinositol-3 kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is very often activated in human cancer [7]. The pathway is often utilized by various cytokine and growth factor receptor signaling, and mutation, expressional change or amplification of any of its elements could cause resistance against tumor therapy [7,8]. Accordingly, all members of this pathway (including Akt) were suggested as targets in monotherapy or combination therapy for various cancers.…”

Section: Introductionmentioning

confidence: 99%

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas

Sümegi

Szabó

2020

Cancers

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Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

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AKT as a Therapeutic Target for Cancer

Cited by 583 publications

References 106 publications

In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

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