Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endometrial carcinosarcomas are aggressive neoplasias composed of high-grade carcinomatous and sarcomatous elements. The pathogenesis and specific genetic alterations underlying these tumors are still not well known. We analyzed alterations in oncogenes involved in the pathogenesis of endometrial carcinomas that might represent predictive markers for specific therapies. Immunohistochemistry for HER2 (tyrosine kinase-type cell surface receptor HER2) and c-KIT (tyrosine-protein kinase Kit) and fluorescence in situ hybridization for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma receptor tyrosine kinase) were carried out for 76 endometrial carcinosarcoma samples on sequential tissue microarray sections. Analysis of 238 mutations across 19 common oncogenes was performed on 34 samples using the Sequenom OncoCarta Panel (Sequenom, Hamburg, Germany). We observed EGFR, HER2, and c-KIT expression in 71%, 1.5%, and 2.7% of tumors, respectively. EGFR amplification was detected in 11 of 76 endometrial carcinosarcomas (14.5%). Four samples showed both amplification and aneuploidy (5.2%). ALK amplification together with chromosome 2 polysomy was found in 1.3% of endometrial carcinosarcomas. In total, 23 mutations in 9 different oncogenes were detected in 15 (44.1%) of 34 endometrial carcinosarcomas. Five endometrial carcinosarcomas (14.7%) had 2 or more mutations. Eleven tumors (32.3%) had mutations affecting the PI3K (phosphoinositide-3-kinase)/AKT (v-akt murine thymoma viral oncogene homolog 1) (6 mutations in PIK3CA (PI3K catalytic alpha polypeptide) and 1 in AKT) and/or RAS/BRAF (serine/threonine-protein kinase B-raf) pathway (3 KRAS [kirsten RAS oncogene homolog], 2 NRAS [neuroblastoma RAS viral oncogene homolog], and 1 BRAF). Mutations in PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) and/or KIT were found in 5 endometrial carcinosarcomas (14.7%). Finally, we found mutations in MET (met proto-oncogene [hepatocyte growth factor receptor]) in 2 tumors (5.9%) and in EGFR in one (2.9%). Our study evidences mutations in oncogenes in endometrial carcinosarcomas that are targets or modulators of response to specific therapies in other human cancers, with PI3K/AKT being the most frequently altered pathway.
 ...
PMID:Oncogene alterations in endometrial carcinosarcomas. 2319 29

PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors.
 ...
PMID:PIK3CA mutations in advanced cancers: characteristics and outcomes. 2370 10

In contrast to other primary epidermal growth factor receptor (EGFR) mutations in lung adenocarcinomas, insertions in exon 20 of EGFR have been generally associated with resistance to EGFR-tyrosine kinase inhibitors. Their molecular spectrum, clinicopathologic characteristics, and prevalence are not well established. Tumors harboring EGFR exon 20 insertions were identified through an algorithmic screen of 1,500 lung adenocarcinomas. Cases were first tested for common mutations in EGFR (exons 19 and 21) and KRAS (exon 2) and, if negative, further analyzed for EGFR exon 20 insertions. All samples underwent extended genotyping for other driver mutations in EGFR, KRAS, BRAF, ERBB2/HER2, NRAS, PIK3CA, MEK1, and AKT by mass spectrometry; a subset was evaluated for ALK rearrangements. We identified 33 EGFR exon 20 insertion cases [2.2%, 95% confidence interval (CI), 1.6-3.1], all mutually exclusive with mutations in the other genes tested (except PIK3CA). They were more common among never-smokers (P < 0.0001). There was no association with age, sex, race, or stage. Morphologically, tumors were similar to those with common EGFR mutations but with frequent solid histology. Insertions were highly variable in position and size, ranging from 3 to 12 bp, resulting in 13 different insertions, which, by molecular modeling, are predicted to have potentially different effects on erlotinib binding. EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases, representing the third most common type of EGFR mutation after exon 19 deletions and L858R. Insertions are structurally heterogeneous with potential implications for response to EGFR inhibitors.
 ...
PMID:EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. 2396 6

The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes, and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts. This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation, or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies. Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations. This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, the cross-talk between them, and the current generation of PI3K and MEK inhibitors that target them. The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials, namely malignant melanoma with BRAF or NRAS mutations, and colorectal, ovarian, pancreatic, and basal-like breast cancers. The emerging clinical profile of PI3K and MEK inhibitor combinations, as reported in Phase I trials, will also be discussed.
 ...
PMID:PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. 2344 7

The HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS-mutant melanoma. Treatment of NRAS-mutant melanoma cell lines with XL888 led to an inhibition of growth, G2-M phase cell-cycle arrest, and the inhibition of cell survival in three-dimensional spheroid and colony formation assays. In vitro, HSP90 inhibition led to the degradation of ARAF, CRAF, Wee1, Chk1, and cdc2 and was associated with decreased mitogen-activated protein kinase (MAPK), AKT, mTOR, and c-jun NH2 kinase (JNK) signaling. Apoptosis induction was associated with increased BIM expression and a decrease in the expression of the prosurvival protein Mcl-1. The critical role of increased BIM and decreased Mcl-1 expression in the survival of NRAS-mutant melanoma cell lines was shown through siRNA knockdown and overexpression studies. In an animal xenograft model of NRAS-mutant melanoma, XL888 treatment led to reduced tumor growth and apoptosis induction. Important differences in the pattern of client degradation were noted between the in vivo and in vitro studies. In vivo, XL888 treatment led to degradation of CDK4 and Wee1 and the inhibition of AKT/S6 signaling with little or no effect observed upon ARAF, CRAF, or MAPK. Blockade of Wee1, using either siRNA knockdown or the inhibitor MK1775, was associated with significant levels of growth inhibition and apoptosis induction. Together, these studies have identified Wee1 as a key target of XL888, suggesting novel therapeutic strategies for NRAS-mutant melanoma.
 ...
PMID:Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. 2353 2

Treatment of V600E/K BRAF-mutated melanomas with RAF inhibitors (either vemurafenib or dabrafenib) results in rapid and dramatic responses in most patients-results that are associated with improved progression-free survival (PFS) and in the case of vemurafenib, overall survival (OS). However, resistance develops at a median time of approximately 6 months. Understanding the mechanisms of resistance is critical to develop strategies to prolong PFS and OS. Negative feedback mechanisms inherent in the MAPK pathway serve to modulate responses to these drugs. However, genetic changes develop within the tumor, which lead to reactivation of the MAPK and resistance to these drugs. The mechanisms that have been demonstrated in many patients by multiple investigators are (1) development of an activating mutation in NRAS, and (2) appearance of a BRAFV600E splice variant that encourages RAF dimerization. Several other mechanisms of resistance have also been described in individual patients or in preclinical models of resistance. In addition, there is evidence that activation of parallel pathways, such as the PI3K/AKT pathway, may represent another mechanism of resistance. Understanding the various mechanisms of resistance will inform our attempts to prevent resistance to RAF inhibitors.
...
PMID:Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation. 2371 62

Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.
...
PMID:BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells. 2394 52

The PI3K/AKT pathway is considered to play a major role in bladder carcinogenesis, but its relationships with other molecular alterations observed in bladder cancer remain unknown. We investigated PI3K/AKT pathway activation in a series of human bladder urothelial carcinomas (UC) according to PTEN expression, PTEN deletions and FGFR3, PIK3CA, KRAS, HRAS, NRAS and TP53 gene mutations. The series included 6 normal bladder urothelial samples and 129 UC (Ta n = 25, T1 n = 34, T2-T3-T4 n = 70). Expression of phospho-AKT (pAKT), phospho-S6-Ribosomal Protein (pS6) (one downstream effector of PI3K/AKT pathway) and PTEN was evaluated by reverse phase protein Array. Expression of miR-21, miR-19a and miR-222, known to regulate PTEN expression, was also evaluated. pAKT expression levels were higher in tumors than in normal urothelium (p < 0.01), regardless of stage and showed a weak and positive correlation with pS6 (Spearman coefficient RS = 0.26; p = 0.002). No association was observed between pAKT or pS6 expression and the gene mutations studied. PTEN expression was decreased in PTEN-deleted tumors, and in T1 (p = 0.0089) and T2-T3-T4 (p < 0.001) tumors compared to Ta tumors; it was also negatively correlated with miR-19a (RS = -0.50; p = 0.0088) and miR-222 (RS = -0.48; p = 0.0132), but not miR-21 (RS = -0.27; p = 0.18) expression. pAKT and PTEN expressions were not negatively correlated, and, on the opposite, a positive and moderate correlation was observed in Ta (RS = 0.54; p = 0.0056) and T1 (RS = 0.56; p = 0.0006) tumors. Our study suggests that PI3K/AKT pathway activation occurs in the entire spectrum of bladder UC regardless of stage or known most frequent molecular alterations, and independently of low PTEN expression.
...
PMID:PI3K/AKT pathway activation in bladder carcinogenesis. 2412 82

Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model.
...
PMID:Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma. 2434 26

Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.
 ...
PMID:Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. 2413 30


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>