Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

Chen, Ying; Huang, Lan; Dong, Yongjian; Tao, Changli; Zhang, Rongxin; Shao, Hongwei; Shen, Han

doi:10.3389/fcell.2020.573599

Cited by 33 publications

(32 citation statements)

References 113 publications

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“…AKT is composed of three conservative structure domains: an N-terminal PH domain, a central kinase domain, and a C-terminal regulatory domain. A single amino acid substitution, E17K, in the lipid-binding PH domain of AKT-1 is a recurrent somatic cell mutation that occurs in breast cancer, meningioma, colorectal, endometrial, and ovarian cancers, and the mutation results in constitutive AKT1 activation [ 108 , 109 ]. This mutation dramatically increases the affinity of E17K AKT to PtdIns(4,5)P2 [ 110 ], activates AKT1 by means of pathological localization to the plasma membrane, and stimulates downstream signaling [ 111 , 112 ].…”

Section: Deregulation Of the Pi3k/akt/mtor Pathway In Cancermentioning

confidence: 99%

The Role of mTOR Signaling as a Therapeutic Target in Cancer

Popova

Jücker

2021

IJMS

154

107

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The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.

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Section: Deregulation Of the Pi3k/akt/mtor Pathway In Cancermentioning

confidence: 99%

The Role of mTOR Signaling as a Therapeutic Target in Cancer

Popova

Jücker

2021

IJMS

154

107

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“…AKT1 E17K variants have been previously characterized as activating and oncogenic. The AKT1 E17K mutation is proposed to induce hyper activation of the mTOR pathway through constitutive AKT1 signaling and activation of the downstream components of the mTOR pathway (29,30). Clinical study of mTOR pathway targeted therapy in AKT1 mutant breast cancer is still early in development.…”

Section: Discussionmentioning

confidence: 99%

“…AKT1 is an intracellular serine/threonine kinase that can phosphorylate and activate the serine/threonine kinase mTORi (1). Upon activation, the mTORi complex can stimulate cell proliferation and growth through a variety of oncogenic mecha-nisms.…”

Section: Genomic Analysismentioning

confidence: 99%

“…AKT1 E17K variant has been extensively characterized preclinically in a variety of cancer cell types and model systems (6)(7)(8)(9)(10)(11). AKT1 E17K is a hotspot mutation occurring at the N-terminal of the AKT1 protein (1,12). In breast cancer cell line models, ectopic expression of AKT1 E17K leads to increased phosphorylation of AKT1 target genes, inhibition of apoptosis, increased colony formation, and increased tumor growth in mouse xenograft models (6,7).…”

Section: Genomic Analysismentioning

confidence: 99%

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Patient with Lobular Carcinoma of the Breast and Activating AKT1 E17K Variant

Trivedi

Hamdani²,

Thomas

et al. 2021

ama

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Objective. To present the characteristics of the AKT1E117K gene variant and a description of the clinical application in a patient with metastatic breast cancer.Results. 63 y/o woman with Stage IV Invasive lobular carcinoma at diagnosis was treated with Palbociclib and aromatase inhibitors (AI). At progression, tissue was sent for comprehensive genomic profiling to Foundation Medicine (FM) which revealed AKT1E17K mutation. In lieu of available clinical data within the patient’s tumor type (HR+ HER2- breast cancer), extrapolated data from the Flatiron Health-FM (FH-FMI) Clinico-genomic Database (CGDB) was dis- cussed at our Molecular Tumor Board (MTB). After multidisciplinary discussion, the consensus recommendation was to start treatment with the combination of mTOR inhibitor everolimus, and AI, exemestane. Patient tolerated treatment without major side effects. By the second clinical visit the patient’s breast showed signs of improvement. PET/CT showed diminished left axillary uptake, decreased right paratracheal lymph node PET avidity, and stable bone disease consistent with a partial response. The most recent office visit in January 2021, breast exam revealed a normal-appearing skin with only faint erythema. All other skin lesions have resolved. Although, the role of AKT1 variant described here is not well defined and therapeutic significance of M-Tor inhibitors not established in metastatic breast cancers, comprehensive approach to this case unraveled new and successful therapeutic option in this patient. Conclusion. This demonstrates that applying available Precision Medicine tools like MTB and real world data sets from patient populations with similar clinical and genomic profiles may provide more options for treatment.

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“…In addition, different levels of negative feedback loop activity during acute or chronic PI3K/AKT/mTOR pathway inhibition may indeed have an effect on dosing schedules for AKT inhibitors [111]. Whereas immunohistochemical loss of PTEN expression or AKT1–3 amplification is frequent in breast cancer, somatic gain-of-function AKT1 E17K mutation is found only in 1–8% of breast cancer patients [115] and results in a constitutive activation of this pathway. AKT1 E17K activity can be successfully suppressed by both allosteric AKT inhibitors, impeding AKT localization to the plasma membrane, and catalytic, ATP-competitive AKT inhibitors in breast cancer models [116].…”

Section: Akt Inhibitors Beyond Cdk4/6i Progressionmentioning

confidence: 99%

Treatment of Luminal Metastatic Breast Cancer beyond CDK4/6 Inhibition: Is There a Standard of Care in Clinical Practice?

Mavratzas

Marmé

2021

Breast Care

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Background: CDK4/6 inhibitors have become the standard for first-line treatment of metastatic luminal breast cancer based on consistent data from several phase 3 trials demonstrating clinically meaningful improvement of progression-free as well as overall survival. In addition, they are about to become a part of adjuvant treatment for patients with high-risk luminal disease based on positive results from the first randomized phase 3 trial on abemaciclib. Nevertheless, the majority of patients with advanced or metastatic luminal breast cancer and prospectively a relevant proportion of patients treated in the adjuvant setting will eventually develop resistance to this endocrine based combination within 12–36 months, depending on the line of treatment. Conclusion: Potential subsequent therapies include PI3K inhibitors, mTOR inhibitors, endocrine monotherapy, PARP inhibitors, and chemotherapy. However, these therapies have mainly been developed in the pre-CDK4/6 inhibitor era and little is known about potential cross-resistance. The concept of continuing CDK4/6 inhibition beyond progression is supported by some preclinical data, but to date there is very limited clinical evidence to support this strategy. Therefore, treatment of metastatic luminal breast cancer after progression on CDK4/6 inhibitors remains a challenge. Key Messages: Here we review current evidence from pro- and retrospective studies and give an outlook on future developments with respect to novel therapeutic agents, including oral SERD and AKT inhibitors, which have the potential to change the therapeutic landscape in the future. Furthermore, clinical treatment algorithms and current research will also be discussed.

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Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

Cited by 33 publications

References 113 publications

The Role of mTOR Signaling as a Therapeutic Target in Cancer

The Role of mTOR Signaling as a Therapeutic Target in Cancer

Patient with Lobular Carcinoma of the Breast and Activating AKT1 E17K Variant

Treatment of Luminal Metastatic Breast Cancer beyond CDK4/6 Inhibition: Is There a Standard of Care in Clinical Practice?

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