The evolving landscape of protein kinases in breast cancer: Clinical implications

Ocaña, Alberto; Amir, Eitan; Šeruga, Boštjan; Martín, Miguel; Pandiella, Atanasio

doi:10.1016/j.ctrv.2012.05.004

Cited by 20 publications

(17 citation statements)

References 96 publications

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“…Based on this hypothesis, it would be expected that PIK3CA mutations may not be associated with improvement in outcome from drugs targeting the PI3K/AKT/mTOR pathway. This hypothesis is supported by data in breast cancer, which show little predictive value of PIK3CA with the mTOR inhibitor everolimus [15], [16], [25]. On the other hand, it is known that not all druggable molecular alterations in cancer are linked with worse outcome like the expression of estrogen receptors in breast cancer.…”

Section: Discussionmentioning

confidence: 84%

“…Inhibition of mTOR with rapalogs has shown clinical efficacy against some solid tumors, including everolimus for angiomyolipoma associated with tuberous sclerosis, metastatic renal cell carcinoma, breast cancer, or pancreatic neuroendocrine carcinomas and temsirolimus for renal cell carcinoma [11]–[14]. Many other agents in clinical development are designed to inhibit the PI3K/AKT/mTOR pathway at different levels and include pure PI3K inhibitors, dual PI3K-mTOR inhibitors, AKT inhibitors or mTOR inhibitors [15], [16]. Despite the approval of some drugs and the clinical development of other agents targeting the PI3K/AKT/mTOR pathway, little is known about which patients are more likely to benefit from targeting this pathway.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis

et al. 2014

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BackgroundAberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear.MethodsPubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model.ResultsAnalysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42–3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13).ConclusionActivation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis

et al. 2014

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“…For the past few years, the main focus for research on the treatment of cancer has gradually transferred from the use of cytotoxic drugs to targeted therapies, that is, targeting specific genes or proteins that play a key role in the growth and progression of cancer (2). In this area, compared with a wide range of studies on genes or proteins that are downstream of the epidermal growth factor receptor (EGFR), corresponding work focusing on upstream genes or proteins has rarely been carried out (3). A disintegrin and metalloproteinase (ADAM) family members are a series of Zn-dependent metalloproteinases and they are, as ectodomain sheddases, best known for their domains that function as metalloproteases (4).…”

Section: Introductionmentioning

confidence: 99%

ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation

Meng

Hossain

et al. 2016

International Journal of Oncology

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A disintegrin and metalloproteinase-17 (ADAM17) can cut and release a wide variety of epidermal growth factor receptor (EGFR) ligands to promote survival, invasion and proliferation of cancer cell, and therefore, is considered to be a potential therapeutic target for cancer. The main goal of the present study was to observe the effects of ADAM17 small interfering RNA (ADAM17-siRNA) on human MCF-7 breast cancer and investigate its activation pathway. In vitro, MCF-7 cells were divided into ADAM17-siRNA groups, nonsense siRNA groups, AG1478 (selective EGFR blocker) groups, LY294002 [phosphatidylinositol 3-kinase (PI3K) phosphorylation inhibitor] groups, PD0325901 [mitogen extracellular kinase (MEK) inhibitor] groups and control groups. In vivo, MCF-7 cells were implanted subcutaneously into nude mice and then these mice were randomly divided into ADAM17-siRNA groups, vector groups and control groups. Our data showed that compared with the control groups, ADAM17-siRNA, AG1478 and LY294002 could inhibit the migration and proliferation of MCF-7 cells, but PD0325901 and nonsense siRNA did not show this effect. Except that specific ADAM17-siRNA could inhibit the expression of ADAM17 mRNA, others did not change it. Western blot analysis further confirmed that EGFR-PI3K-AKT signaling pathway is involved in ADAM17-siRNA inhibiting migration and proliferation of MCF-7 cells. Similarly to the former, the growth of MCF-7 breast cancer in nude mice was significantly inhibited by ADAM17-siRNA. Compared with the control group and the vector group, the tumor volume was smaller in the ADAM17-siRNA group, the tissues developed large areas of necrosis, immunohistochemistry showed low expressions of ADAM17 and Ki-67 and western blot analysis proved that the expression of ADAM17 protein in the tissue was also reduced. The present study suggests that ADAM17-siRNA inhibits MCF-7 breast cancer and is activated through the EGFR-PI3K-AKT signaling pathway.

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“…Given the dismal prognosis of advanced ovarian cancer patients, the importance of tyrosine kinases in initiating/ progressing carcinogenesis and the gains of targeting them in multiple human cancers [19], we evaluated the activity of neratinib (HKI-272), an irreversible pan c-erb inhibitor, against multiple primary ovarian cancer cell lines with differential expression of HER2. We demonstrate for the first time that HER2/neu-amplified EOPFC cell lines treated with neratinib in vitro show a significant decrease in the transcription factor S6 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

et al. 2017

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Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib’s preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib’s efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC50, cell signaling changes, and cell cycle distribution. Neratinib’s in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC50:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

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The evolving landscape of protein kinases in breast cancer: Clinical implications

Cited by 20 publications

References 96 publications

Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis

Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis

ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

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