Is There a Future for AKT Inhibitors in the Treatment of Cancer?

Jansen, Valerie M.; Mayer, Ingrid A.; Arteaga, Carlos L.

doi:10.1158/1078-0432.ccr-16-0100

Cited by 40 publications

(34 citation statements)

References 14 publications

(16 reference statements)

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“…Administration of MK2206 caused the development of a rash and hyperglycaemia resulting in some patients discontinuing the treatment. 29 HSG cells showed no scattering or migration changes upon NGF treatment; therefore, these cells have not shown any expression…”

Section: Discussionmentioning

confidence: 97%

“…Despite the preclinical studies supporting the antitumor effect of MK2206 when combined with endocrine therapy, drugs combined with MK2206 had no significant clinical effect in patients with breast cancer in phase I trials. Administration of MK2206 caused the development of a rash and hyperglycaemia resulting in some patients discontinuing the treatment . HSG cells showed no scattering or migration changes upon NGF treatment; therefore, these cells have not shown any expression of Akt phosphorylation at T308 or S473 residues.…”

Section: Discussionmentioning

confidence: 99%

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Nerve growth factor‐induced migration in oral and salivary gland tumour cells utilises the PI3K/Akt signalling pathway: Is there a link to perineural invasion?

Alkhadar

Macluskey

White

et al. 2019

J Oral Pathology Medicine

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Objectives The aims of this study were to investigate the role of nerve growth factor on perineural invasion in oral and salivary gland tumour cell lines and whether there is an involvement of PI3K/Akt pathway. Materials and Methods Four cell lines were investigated: HSG and TYS (salivary gland tumours), SAS‐H1 (oral squamous cell carcinoma) and HaCaT (human skin keratinocyte). Initially, Boyden chamber assay was done to examine the effect of different concentration of nerve growth factor on cell migration. Western blot/ immunofluorescence techniques were used to investigate the phosphorylation status of the Akt pathway within the cells in response to nerve growth factor. The effect of this growth factor and the addition of an Akt inhibitor on cell morphology and migration were also examined using scatter/scratch assays. Results Nerve growth factor triggered the PI3K/Akt pathway in oral and salivary tumour cells and induced oral and salivary tumour cell scattering and migration. Inhibitor assays confirmed that oral and salivary gland tumour cell scattering and migration is Akt dependent. Conclusions Nerve growth factor can stimulate scattering and migration in cells derived from oral and salivary gland tumours, thereby potentially enhancing perineural invasion. Phosphorylated Akt controls cancer cell migration and scattering. Blocking the Akt pathway may inhibit cell migration and therefore perineural invasion and metastasis.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Nerve growth factor‐induced migration in oral and salivary gland tumour cells utilises the PI3K/Akt signalling pathway: Is there a link to perineural invasion?

Alkhadar

Macluskey

White

et al. 2019

J Oral Pathology Medicine

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“…Therefore, circRNA_100269 could be a novel marker for the diagnosis and treatment for GC. At present, inhibition of PI3K/Akt signaling is considered as a potential therapeutic approach in cancer treatment (28)(29)(30)(31)(32)(33). CircRNA_100269/PI3K/Akt axis could be a putative therapeutic target for the treatment of GC.…”

Section: Resultsmentioning

confidence: 99%

Upregulated circRNA_100269 suppresses the growth and metastasis of gastric cancer by inactivating PI3K/Akt signaling pathway

wang

liu

2020

Preprint

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Background: The expression of circRNA_100269 in gastric cancer (GC) tissues and cells, together with its regulatory roles on GC cells were investigated. Methods: The levels of circRNA_100269 in GC and matched para-carcinoma tissues, as well as in human GC cell lines and normal gastric epithelial cells were evaluated using RT-qPCR. The models with overexpression or knockdown of circRNA_100269 were generated using lentiviral vectors. Cell viability was examined using MTT assay; cell migration and invasive activity were determined by wound healing and Transwell assay. Cell cycle arrest and apoptosis were assessed; molecules involved in PI3K/Akt signaling, apoptosis and EMT were evaluated using RT-qPCR and immunoblotting. Tumour growth and expression of relevant proteins were examined in circRNA_100269 knockout mice. Results: The results indicated the expression of circRNA_100269 was dramatically decreased in GC samples compared with para-carcinoma tissues (p<0.05), while the levels of PI3K were notably increased (p<0.05). Moreover, the level of circRNA_100269 was relevant to histology grade and occurrence of metastasis in GC patients (p<0.05), where circRNA_100269 and PI3K was inversely correlated (p<0.05). Additionally, circRNA_100269 was downregulated in GC cells compared with normal gastric epithelial cells. Overexpressed circRNA_100269 remarkably suppressed the proliferation, migration, invasion and EMT of GC cells (p<0.05), induced cell cycle arrest at G0/G1 phase and promoted cell apoptosis (p<0.05). In addition, PI3K/Akt signaling was involved in circRNA_100269-mediated proliferation, migration, invasion, EMT and apoptosis in GC cells (p<0.05). Knockdown of circRNA_100269 also significantly promoted tumor growth in vivo (p<0.05). Conclusions: the data of the present study suggested that the expression level of circRNA_100269 was decreased in GC tissues and cells. In addition, circRNA_100269 inhibited the progression of GC by suppressing PI3K/Akt signaling. Therefore, circRNA_100269/PI3K/Akt axis may be a potential therapeutic target for GC treatment.

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“…Comprehensive Omics-based data sets are available and these will clearly be expanded by ongoing and future analyses. The bioinformatic integration of these data obtained by genomics, [82], and the mTOR inhibitor everolimus [31]. STAT3 inhibitors are still at earlier stage of development, but the anti-IL-6 antibody tocilizumab is used for treatment of arthritis.…”

Section: Resultsmentioning

confidence: 99%

Tumor–Host Cell Interactions in Ovarian Cancer: Pathways to Therapy Failure

Strandmann¹,

Reinartz

Wager

et al. 2017

Trends in Cancer

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Although most ovarian cancer patients are highly responsive to chemotherapy, they frequently present with recurrent metastatic lesions that result in poor overall survival, a situation that has not changed in the last 20 years. This review discusses new insights into the regulation of ovarian cancer chemoresistance with a focus on the emerging role of immune and other host cells. Here, we summarize the complex molecular pathways that regulate the interaction between tumor and host cells, discuss the limitations of current in vitro and in vivo models for translational studies, and present perspectives for the development of innovative therapies.

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Is There a Future for AKT Inhibitors in the Treatment of Cancer?

Cited by 40 publications

References 14 publications

Nerve growth factor‐induced migration in oral and salivary gland tumour cells utilises the PI3K/Akt signalling pathway: Is there a link to perineural invasion?

Nerve growth factor‐induced migration in oral and salivary gland tumour cells utilises the PI3K/Akt signalling pathway: Is there a link to perineural invasion?

Upregulated circRNA_100269 suppresses the growth and metastasis of gastric cancer by inactivating PI3K/Akt signaling pathway

Tumor–Host Cell Interactions in Ovarian Cancer: Pathways to Therapy Failure

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