PIK3CA mutation status in Japanese lung cancer patients

Kawano, Osamu; Sasaki, Hidefumi; Endo, Katsuhiko; Suzuki, Eriko; Haneda, Hiroshi; Yukiue, Haruhiro; Kobayashi, Yoshihiro; Yano, Motoki; Fujii, Yoshitaka

doi:10.1016/j.lungcan.2006.07.006

Cited by 243 publications

(162 citation statements)

References 31 publications

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“…Such difference is in agreement with the finding that incidence of PI3KCA mutations or amplification is consistently higher in SCC than in ADC (6.5% versus 1.5%, respectively), 11,12 and suggest that PI3K and AKT1 might share common pathways of activation in the metaplastic cells lining bronchial epithelium from which SCC Figure 1. (A) E17K mutation due to G→A transition in the codon 17 of the AKT1 gene in 2 different squamous cell carcinomas of the lung, P-LC34, M-LC84.…”

Section: Discussionsupporting

confidence: 89%

“…9,10 On the other hand, SCC are frequently characterised by amplification and/or mutations that affect the catalytic subunit of the lipid kinase phosphatidylinositol 3-kinase (PI3KCA) (4%). 11,12 As to the negative regulator of the PI3K pathway, the lipid Phosphatase and Tensin homologue (PTEN), inactivating mutations in lung cancer are rare but its expression is lost by deletion and/or methylation both in ADC and SCC. 13 Constitutive signalling from the PI3K pathway plays a central role in different human neoplasms including lung cancer.…”

Section: Introductionmentioning

confidence: 99%

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Activating E17K mutation in the gene encoding the protein kinase AKT in a subset of squamous cell carcinoma of the lung

Malanga¹,

Scrima²,

Marco³

et al. 2008

Cell Cycle

175

108

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Somatic mutation (E17K) that constitutively activates the protein kinase AKT1 has been found in human cancer patients. We determined the role of the E17K mutation of AKT1 in lung cancer, through sequencing of AKT1 exon 4 in 105 resected, clinically annotated non-small cell lung cancer specimens. We detected a missense mutations G→A transition at nucleotide 49 (that results in the E17K substitution) in two squamous cell carcinoma (2/36) but not in adenocarcinoma (0/53). The activity of the endogenous kinase carrying the E17K mutation immunoprecipitated by tumour tissue was significantly higher compared with the wildtype kinase immunoprecipitated by the adjacent normal tissue as determined both by in vitro kinase assay using a consensus peptide as substrate and by in vivo analysis of the phosphorylation status of AKT1 itself (pT308, pS473) or of known downstream substrates such as GSK3 (pS9/S22) and p27 (T198). Immunostaining or immunoblot analysis on membrane-enriched extracts indicated that the enhanced membrane localization exhibited by the endogenous E17K-AKT1 may account for the observed increased activity of mutant E17K kinase in comparison with the wild-type AKT1 from adjacent normal tissue. In conclusion, this is the first report of AKT1 mutation in lung cancer. Our data provide evidence that, although AKT1 mutations are apparently rare in lung cancer (1.9%), the oncogenic properties of E17K-AKT1 may contribute to the development of a fraction of lung carcinoma with squamous histotype (5.5%).

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Activating E17K mutation in the gene encoding the protein kinase AKT in a subset of squamous cell carcinoma of the lung

Malanga¹,

Scrima²,

Marco³

et al. 2008

Cell Cycle

175

108

View full text Add to dashboard Cite

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“…196 Primary TKI resistance may also be mediated by the presence of other genetic alterations that affect signaling downstream from EGFR, such as mutation of KRAS, PIK3CA, and loss of PTEN expression. [197][198][199] Mutations in KRAS, which are frequently found in adenocarcinomas with wildtype EGFR, are a mechanism of primary resistance to gefitinib and erlotinib. 63 PTEN is one of the key downstream components of the EGFR pathway and has a significant role in cell survival, proliferation, and growth.…”

Section: Primary Resistance To Egfr Targeted Therapymentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…4 -6 Accordingly, amplification and/or activating mutations in PI3K or AKT1 genes or the loss of PTEN that lead to the constitutive activation of PI3K have been reported in NSCLC. [7][8][9] The PTEN gene, located at 10q23.3, is a tumor suppressor that encodes a lipid phosphatase that antagonizes the action of phosphatidylinositol 3-kinase by dephosphorylating the second messenger phosphatidylinositol 3,4,5-triphosphate. 10,11 Loss of PTEN expression occurs frequently in lung cancer and represents an independent poor prognostic factor for patients with NSCLC.…”

mentioning

confidence: 99%

Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

Amodio

Scrima²,

Palaia

et al. 2010

The American Journal of Pathology

127

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Loss of the PTEN tumor suppressor gene occurs frequently in non-small-cell lung carcinoma (NSCLC), although neither genetic alterations nor epigenetic silencing are significant predictors of PTEN protein levels. Since recent reports implicated neural precursor cell expressed, developmentally down-regulated 4-1 (NEDD4-1) as the E3 ubiquitin ligase that regulates PTEN stability, we investigated the role of NEDD4-1 in the regulation of PTEN expression in cases of NSCLC. Our findings indicate that NEDD4-1 plays a critical role in the development of NSCLC and provides novel insight on the mechanisms that contribute to inactivate PTEN in lung cancer. Immunohistochemical analysis on tissue microarrays containing 103 NSCLC resections revealed NEDD4-1 overexpression in 80% of tumors, which correlated with the loss of PTEN protein (n ‫؍‬ 98; P < 0.001). Accordingly, adoptive NEDD4-1 expression in NSCLC cells decreased PTEN protein stability, whereas knock-down of NEDD4-1 expression decreased PTEN ubiquitylation and increased PTEN protein levels. In 25% of cases, NEDD4-1 overexpression was due to gene amplification at 15q21. In addition, manipulation of NEDD4-1 expression in different lung cell systems demonstrated that suppression of NEDD4-1 expression significantly reduced proliferation of NSCLC cells in vitro and tumor growth in vivo, whereas NEDD4-1 overexpression facilitated anchorage-dependent and independent growth in vitro of nontransformed lung epithelial cells that lack pRB and TP53 (BEAS-2B). NEDD4-1 overexpression also augmented the tumorigenicity of lung cancer cells that have an intact PTEN gene (NCI-H460 cells).

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PIK3CA mutation status in Japanese lung cancer patients

Cited by 243 publications

References 31 publications

Activating E17K mutation in the gene encoding the protein kinase AKT in a subset of squamous cell carcinoma of the lung

Activating E17K mutation in the gene encoding the protein kinase AKT in a subset of squamous cell carcinoma of the lung

Molecular pathology of lung cancer: key to personalized medicine

Oncogenic Role of the E3 Ubiquitin Ligase NEDD4-1, a PTEN Negative Regulator, in Non-Small-Cell Lung Carcinomas

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