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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While prognostic factors can help to classify the standard risk of subpopulations of patients with the same tumor entity, it is still not possible to predict the response of individual patients to specific therapies. The reason for such wide variation in cancer therapy responses remains largely unknown. The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy to targeted therapy in order to kill tumor cells more efficiently with fewer side effects on normal tissue. In the present review, we focus on colorectal carcinoma, which is one of the most frequent tumor types worldwide and represents a leading cause of cancer-related deaths. The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. A considerable achievement during the past years was the development of targeted therapies against EGFR using monoclonal antibodies and small molecule inhibitors. Two major pathways mediate signal transduction through EGFR: the RAS/RAF/MAPK/ERK and the PI3K/AKT/ PTEN/mTOR pathways. Sometimes, predictive biomarkers can provide information on the expected response of tumors to standard chemotherapy. Such molecular markers for EGFR-targeted treatment have been described. However, disease progression and resistance towards EGFR-directed drugs frequently develop due to mutations in genes downstream of EGFR. In this review, we describe the mechanisms by which colorectal cancers gain resistance against EGFR-targeted therapies as well as strategies to bypass mutationinduced resistance in these two signaling pathways.
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PMID:Signal transduction pathways of the epidermal growth factor receptor in colorectal cancer and their inhibition by small molecules. 2303 49

Endometrial cancer is the most common gynecologic malignancy in the United States. Overactivation of the PI3K/AKT/mTOR pathway, a signaling pathway that plays an important role in cellular growth and survival, has recently been implicated in endometrial cancer pathogenesis, and as such, inhibition of the PI3K/AKT/mTOR pathway is of therapeutic interest. Preclinical and clinical studies are proving useful in elucidating the antitumor effects of different PI3K/AKT/mTOR pathway inhibitors, and in defining which patient populations these inhibitors might be most effective in. For example, an increasing amount of preclinical data suggest that loss of PTEN or genetic alteration of PIK3CA may be indicators of sensitivity to PI3K/AKT/mTOR pathway inhibition, while activating KRAS mutations may predict resistance. In the latter case, combined inhibition of the RAS/RAF/MEK and PI3K/AKT/mTOR pathways has been suggested as a therapeutic strategy. In addition, the PI3K/AKT/mTOR pathway has been implicated in conferring resistance to conventional therapies, and so PI3K/AKT/mTOR pathway inhibitors in combination with hormonal and/or cytotoxic agents are being evaluated. In conclusion, preclinical models are providing insights into the antitumor activity of PI3K/AKT/mTOR pathway inhibition, and are helping define patient populations most likely to benefit from these therapies. Clinical validation of these findings is ongoing.
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PMID:The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. 2308 3

MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor-dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds.
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PMID:Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist. 2311 Aug 8

The clinical significance of KRAS gene testing prior to using anti-epidermal growth factor receptor(EGFR)antibodies for colorectal cancer patients has been established in past randomized clinical trials. Thus, testing for the 7 most common mutations of KRAS codons 12 and 13 is now recommended as a clinical practice. However, pooled analysis of randomized controlled studies in Western countries in patients treated with cetuximab has suggested that patients with tumors showing the KRAS p. G13D mutation[a glycine(G)to aspartate(D)transition mutation] have longer overall survival and progression-free survival when compared to patients with other KRAS mutations. Furthermore, even among patients whose tumors are wild-type for KRAS codons 12 and 13, response rates are only 13~17% for anti-EGFR antibody monotherapy. These facts suggest that additional activating mutations in the RAS-RAF-MAPK or PI3K-AKT-mTOR pathways may also confer resistance to anti-EGFR antibody therapies. Indeed, recent retrospective studies have shown that mutations in KRAS codon 61 and 146, BRAF, NRAS, and PIK3CA may also predict resistance to anti-EGFR antibodies in colorectal cancer patients. On the other hand, the continuous use of anti-EGFR therapies for KRAS wild-type patients may lead to secondary resistance. Acquired EGFR or KRAS mutations have occasionally been detected among specimens from these patients. We review the latest personalized therapy available for colorectal cancer patients using KRAS mutational testing. We also illustrate future perspectives for patient selection using KRAS, BRAF, NRAS, PIK3CA, and other mutations.
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PMID:[Predictive biomarkers for anti-EGFR antibodies]. 2315 13

Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer.
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PMID:Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. 2317 49

Genetic alterations activating K-RAS and PI3K/AKT signaling are also known to induce the activity of mTOR kinase through TORC1 and TORC2 complexes in human pancreatic ductal adenocarcinoma (PDAC). Here, we determined the effects of the dual PI3K and mTOR inhibitor, NVP-BEZ235 (BEZ235), and the pan-histone deacetylase inhibitor panobinostat (PS) against human PDAC cells. Treatment with BEZ235 or PS inhibited cell cycle progression with induction of the cell cycle inhibitory proteins, p21waf1 and p27kip1. BEZ235 and PS also dose dependently induced loss of cell viability of the cultured PDAC cells, associated with depletion of phosphorylated (p) AKT, as well as of the TORC1 substrates 4EBP1 and p70S6 kinase. While inhibiting p-AKT, treatment with PS induced the levels of the pro-apoptotic proteins BIM and BAK. Co-treatment with BEZ235 and PS synergistically induced apoptosis of the cultured PDAC cells. This was accompanied by marked attenuation of the levels of p-AKT and Bcl-xL but induction of BIM. Although in vivo treatment with BEZ235 or PS reduced tumor growth, co-treatment with BEZ235 and PS was significantly more effective in controlling the xenograft growth of Panc1 PDAC cells in the nude mice. Furthermore, co-treatment with BEZ235 and PS more effectively blocked tumor growth of primary PDAC heterotransplants (possessing K-RAS mutation and AKT2 amplification) subcutaneously implanted in the nude mice than each agent alone. These findings demonstrate superior activity and support further in vivo evaluation of combined treatment with BEZ235 and PS against PDAC that possess heightened activity of RAS-RAF-ERK1/2 and PI3K-AKT-mTOR pathways.
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PMID:Superior efficacy of co-treatment with dual PI3K/mTOR inhibitor NVP-BEZ235 and pan-histone deacetylase inhibitor against human pancreatic cancer. 2323 26

The p21-activated kinase (PAK) serine/threonine kinases are important effectors of the small GTPases Rac and Cdc42, and play significant roles in controlling cell growth, motility, and transformation. Knockdown of PAK4 or PAK1 inhibited the proliferation of mutant KRAS or BRAF colon cancer cells in vitro. Dependence on PAK4 or PAK1 protein for colon cancer cell proliferation was independent of PAK4 or PAK1 protein expression levels. Mutant KRAS HCT116 colorectal cells were the most sensitive to PAK4 or PAK1 knockdown resulting in the potent inhibition of anchorage-dependent and -independent proliferation as well as the formation and proliferation of HCT116 colon cancer spheroids. This inhibition of proliferation did not correlate with inhibition of RAF/MEK/ERK or PI3K/AKT signaling. In HCT116 cells, knockdown of PAK4 or PAK1 caused changes to the actin cytoskeleton resulting in reduced basal spread and cell elongation and increased cell rounding. These cytoskeletal rearrangements seemed to be independent of LIMK/cofilin/paxillin phosphorylation. PAK4 or PAK1 knockdown initially induced growth arrest in HCT116 cells followed by cell death at later time points. Inhibition of the antiapoptotic proteins Bcl-2 and Bcl-X(L) with the pharmacologic inhibitor ABT-737 increased effector caspase activation and apoptosis, and reduced cell survival with PAK4 or PAK1 knockdown. These results support a role for the PAKs in the proliferation of mutant KRAS-driven colorectal carcinoma cells via pathways not involving RAF/MEK/ERK and PI3K/AKT signaling.
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PMID:Knockdown of PAK4 or PAK1 inhibits the proliferation of mutant KRAS colon cancer cells independently of RAF/MEK/ERK and PI3K/AKT signaling. 2323 84

The epidermal growth factor receptor (EGFR) triggers a downstream signaling cascade such as the RAS-RAF-MAPK and PI3K-AKT pathways, which are involved in cell proliferation, differentiation, survival and invasion. Two monoclonal antibodies (moABS) targeting EGFR, cetuximab and panitumumab, are established to be a new treatment for metastatic colorectal cancers. Among activating mutations in the downstream of EGFR, the KRAS gene mutation has shown to be predictive biomarker for resistance to anti-EGFR antibody therapy. This review focuses on the current status of chemotherapy with anti-EGFR antibody for colorectal cancers. The identification of patients who are likely to benefit from EGFR-targeted moABS is increasingly crucial for improving therapeutic strategies.
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PMID:[Anti-EGFR antibody therapy for colorectal cancer]. 2325 89

The treatment of ovarian cancer is set to undergo rapid changes, as strategies incorporating molecular targeted therapies begin to take shape. These are based on a better appreciation of approaches targeting the tumor microenvironment as well as specific subtypes of the disease, with distinct molecular aberrations. Targeting the VEGF pathway through bevacizumab is clearly effective, with positive randomized trials at all disease stages; targeting defective homologous recombination repair pathways with PARP inhibitors is also proving successful in a substantial proportion of patients with high-grade serous ovarian cancer. In this article, we will review progress in these two leading areas and also discuss the potential for targeting other pathways and receptors that may be activated in ovarian cancer, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor. Here, single-agent therapy may play a role in selected cases but essential components of future strategies should include combination treatments aimed at dealing with the key problem of drug resistance, together with rational approaches to patient selection.
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PMID:New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. 2330 60

Costello syndrome is a congenital disorder comprising a characteristic face, severe feeding difficulties, skeletal, cardiac and skin abnormalities, intellectual disability and predisposition to malignancies. It is caused by heterozygous germline HRAS mutations mostly affecting Gly(12) or Gly(13), which impair HRAS-GTPase activity and result in increased downstream signal flow independent of incoming signals. Functional analyses of rarer HRAS mutations identified in individuals with attenuated Costello syndrome phenotypes revealed altered GDP/GTP nucleotide affinities (p.K117R) and inefficient effector binding (p.E37dup). Thus, both phenotypic and functional variability associated with HRAS mutations are evident. Here, we report on a novel heterozygous HRAS germline mutation (c.187_207dup, p.E63_D69dup) in a girl presenting with a phenotype at the milder end of the Costello syndrome spectrum. The p.E63_D69dup mutation impaired co-precipitation of recombinant HRAS with NF1 GTPase-activating protein (GAP) suggesting constitutive HRAS(E63_D69dup) activation due to GAP insensitivity. Indeed, we identified strongly augmented active HRAS(E63_D69dup) that co-precipitated with effectors RAF1, RAL guanine nucleotide dissociation stimulator and phospholipase C1. However, we could not pull down active HRAS(E63_D69dup) using the target protein PIK3CA, indicating a compromised association between active HRAS(E63_D69dup) and PIK3CA. Accordingly, overexpression of HRAS(E63_D69dup) increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF, whereas AKT phosphorylation downstream of phosphoinositide 3-kinase (PI3K) was not enhanced. By analyzing signaling dynamics, we found that HRAS(E63_D69dup) has impaired reagibility to stimuli resulting in reduced and disrupted capacity to transduce incoming signals to the RAF-MAPK and PI3K-AKT cascade, respectively. We suggest that disrupted HRAS reagibility, as we demonstrate for the p.E63_D69dup mutation, is a previously unappreciated molecular pathomechanism underlying Costello syndrome.
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PMID:Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome. 2333 89


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