Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases

Ippen, Franziska M.; Grosch, Julia; Subramanian, Megha; Kuter, Benjamin M.; Liederer, Bianca M.; Plise, Emile G.; Mora, Joana L.; Nayyar, Naema; Schmidt, Stephen; Giobbie‐Hurder, Anita; Martinez‐Lage, Maria; Carter, Scott L.; Cahill, Daniel P.; Wakimoto, Hiroaki; Brastianos, Priscilla K.

doi:10.1093/neuonc/noz105

Cited by 77 publications

(50 citation statements)

References 33 publications

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“…Zhao et al 37 found an oncogenic feedforward loop between the p27-Thr198/c-Jun Nterminal kinase2/Signal Transducers and Activators of Transcription3/TWIST axis and AKT, whose activation promoted EMT and cancer metastasis. Franziska et al reported that the pan-AKT inhibitor GDC-0068 inhibited the phosphorylation level of p70S6K-Thr389 and PRAS40-Thr246 residues and reduced the brain metastasis of PIK3CA-mutant breast cancer 38 . These data demonstrated the AKT-mediated pro-cancerous cascades and the potential downstream targets of it in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

Wang

Sun

et al. 2020

Cell Death Dis

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Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial–mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and β-catenin. We observed that β-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of β-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the β-catenin/SLUG axis. Furthermore, the expression levels of NE and β-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and β-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/β-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

Wang

Sun

et al. 2020

Cell Death Dis

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“…The activation of PI3K/AKT pathway has been reported to take part in tumor cell proliferation and apoptosis [29][30][31]. Here, we proved that knockdown of miR-489 promoted the activation of PI3K/AKT signaling pathway and miR-489 restoration showed the opposite effect.…”

Section: Discussionmentioning

confidence: 56%

MiR-489 inhibited the development of gastric cancer via regulating HDAC7 and PI3K/AKT pathway

Zhang

Yuan

et al. 2020

World J Surg Onc

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Background: Mounting evidences have displayed that the dysregulation of miRNAs plays important roles in the pathogenesis of gastric cancer (GC). The purpose of this study was to explore the biological functions and potential mechanism of miR-489 in GC progression. Methods: Quantitative real-time PCR (qRT-PCR) and western blot were performed to examine the mRNA expression and protein levels of miR-489 and HDAC7. The relationship between miR-489 and HDAC7 was analyzed by Spearman rank correlation. 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell assays were conducted for determining the effect of miR-489 and HDAC7 on GC cell viability, migration, and invasion. TargetScan and luciferase reporter assay were used to confirm the target gene of miR-489 in GC cells. Results: The findings showed that miR-489 was dramatically decreased in GC tissues and GC cell lines (SGC-7901 and MKN45). Moreover, it was closely correlated with overall survival (OS) and progression-free survival (PFS) of GC patients. Downregulation of miR-489 significantly promoted GC cell proliferation, invasion, and migration. Additionally, HDAC7 was confirmed as the direct target of miR-489. Knockdown of HDAC7 exerted inhibited effect on GC progression and it markedly overturned miR-489 inhibitor-medicated effect on GC cells. More interestingly, via targeting HDAC7, miR-489 blocked the activation of PI3K/AKT pathway in GC cells. Conclusions: Correctively, miR-489 played as a tumor suppressor in GC cell growth by targeting HDAC7, and miR-489 might function as a novel biomarker for diagnosis or therapeutic targets of human GC.

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“…PIK3CA encodes p110α, a subunit of phosphoinositide 3-kinase (PI3K), and the proliferation signal from PI3K is transduced to protein kinase B (PKB; AKT) [59,61,62]. In a previous study, the pan-AKT inhibitor GDC-0068 decreased the viability of MDA-MB-453 cells in vitro [63]. Considering that activation of the PI3K/AKT pathway is observed in breast cancer patients with brain metastasis [64,65], this signaling pathway might be a potential target for curing brain metastasis.…”

Section: Discussionmentioning

confidence: 99%

Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines

Kuroiwa

Nakayama

Adachi

et al. 2020

Cancers

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HER2 is overexpressed in 25–30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453 cells rapidly proliferated in the brain parenchyma, while the other seven cell lines moderately or slowly proliferated. Among these nine cell lines, the proliferative activity in brain tissue was not correlated with either the HER2 level or the HER2 phosphorylation status. To extract signature genes associated with brain colonization, we conducted microarray analysis and found that these two cell lines shared 138 gene expression patterns. Moreover, some of these genes were correlated with poor prognosis in HER2-positive breast cancer patients. Our findings might be helpful for further studying brain metastasis in HER2-positive breast cancer.

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Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases

Cited by 77 publications

References 33 publications

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

MiR-489 inhibited the development of gastric cancer via regulating HDAC7 and PI3K/AKT pathway

Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines

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