Search results for: MEK-162 (ARRY-438162) Mechanisms: MEK inhibitor
#28581516 2017/06/05 Save this To Up
Pancreatic cancer heterogeneity and response to Mek inhibition.Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab-paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy.
Top five cancer tissue ar CAR,CAR,Constitutive acti Top 10 cancer tissue arra Oral cavity (tongue and p Oral squamous cell cancer Multiple pancreatic cance Mid advanced stage pancre High density (69 cases 20 High density (69 cases 20 Pancreatic disease spectr High density pancreatic c Pancreatic cancer test ti
#27167191 2016/05/11 Save this To Up
Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo.
1511 related Products with: Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.AZD-6244 Mechanisms: MEK Lung cancer tissue array, Colon cancer, metastasize Rectum disease spectrum ( Infiltrating duct carcino Bladder cancer tissue arr Breast cancer tissue arra Breast disease spectrum t Colon cancer and lung can Colorectal carcinoma and Colon cancer tissue array High density cervical can
#27422710 2016/07/16 Save this To Up
Phosphoproteomics Reveals MAPK Inhibitors Enhance MET- and EGFR-Driven AKT Signaling in KRAS-Mutant Lung Cancer.Pathway inhibition of the RAS-driven MAPK pathway using small-molecule kinase inhibitors has been a key focus for treating cancers driven by oncogenic RAS, yet significant clinical responses are lacking. Feedback reactivation of ERK driven by drug-induced RAF activity has been suggested as one of the major drug resistance mechanisms, especially in the context of oncogenic RAS. To determine whether additional adaptive resistance mechanisms may coexist, we characterized global phosphoproteomic changes after MEK inhibitor selumetinib (AZD6244) treatment in KRAS-mutant A427 and A549 lung adenocarcinoma cell lines employing mass spectrometry-based phosphoproteomics. We identified 9,075 quantifiable unique phosphosites (corresponding to 3,346 unique phosphoproteins), of which 567 phosphosites were more abundant and 512 phosphosites were less abundant after MEK inhibition. Selumetinib increased phosphorylation of KSR-1, a scaffolding protein required for assembly of MAPK signaling complex, as well as altered phosphorylation of GEF-H1, a novel regulator of KSR-1 and implicated in RAS-driven MAPK activation. Moreover, selumetinib reduced inhibitory serine phosphorylation of MET at Ser985 and potentiated HGF- and EGF-induced AKT phosphorylation. These results were recapitulated by pan-RAF (LY3009120), MEK (GDC0623), and ERK (SCH772984) inhibitors, which are currently under early-phase clinical development against RAS-mutant cancers. Our results highlight the unique adaptive changes in MAPK scaffolding proteins (KSR-1, GEF-H1) and in RTK signaling, leading to enhanced PI3K-AKT signaling when the MAPK pathway is inhibited.
1667 related Products with: Phosphoproteomics Reveals MAPK Inhibitors Enhance MET- and EGFR-Driven AKT Signaling in KRAS-Mutant Lung Cancer.PathwayReady™ PI3 K Akt PathwayReady™ EGFR Sign AKT PKB Signaling Phospho GPCR Signaling to MAPK ER Lung cancer tissue array, Lung cancer tissue array Colon cancer and lung can AKT1 & MAPK14 Protein Pro MAPK14 & EGFR Protein Pro AKT1 & MAPKAPK2 Protein P DiscoveryPak™ EGFR Tyro PathwayReady™ MAP Kinas
#27149444 2016/05/06 Save this To Up
Loss of MAPK Pathway Activation in Post-Mitotic Retinal Cells as Mechanism in MEK Inhibition-Related Retinopathy in Cancer Patients.Recently, treatment with MEK inhibitors has been shown to be an effective treatment option for metastatic melanoma. Treatment efficacy is dependent on inhibition of MAPK-related melanoma proliferation. However, targeting of MEK can be accompanied by a time-dependent and reversible serous retinopathy of unknown origin.We analyzed the molecular mechanism by which the MEK inhibitor binimetinib may lead to retinopathy, using neuroretina and cell models of retinal pigment epithelium (RPE).Binimetinib inhibited the MAPK pathway while discontinuation of treatment resulted in reactivation. However, cell proliferation was not inhibited correspondingly during binimetinib treatment of ARPE19 cells. Remarkably, post-mitotic neuroretinal tissue displayed a strong MAPK activation that was lost after binimetinib treatment.We propose that binimetinib-associated retinopathy is correlated with inhibition of the MAPK pathway in multiple retinal components. Retinal cells are able to regain the activation after binimetinib treatment, mimicking the reversibility of the retinopathy. As most retinal cells are nonregenerating, other mechanisms than stimulation of proliferation must be involved.
2235 related Products with: Loss of MAPK Pathway Activation in Post-Mitotic Retinal Cells as Mechanism in MEK Inhibition-Related Retinopathy in Cancer Patients.GPCR Signaling to MAPK ER GLP 1 ELISA Kit, Rat Gluc Directed In Vivo Angiogen AS-703026 Mechanisms: MEK AZD-6244 Mechanisms: MEK RDEA-119 (BAY-869766) Mec CI-1040 (PD184352) Mechan RO-5126766 Mechanisms: Ra MEK-162 (ARRY-438162) Mec ASP-3026 Mechanisms: ALK GDC-0973 (XL-518) Mechani AZD-8330 Mechanisms: MEK
#26925841 2016/03/01 Save this To Up
Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.Novel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models.
1095 related Products with: Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression.Primary antibody low den JAK pathway ISRE reporter NycoPrep™ 1.077, for is Rabbit Anti-MEK2 MAPKK2 P Rabbit Anti-MEK2 MAPKK2 P Rabbit Anti-MEK2 MAPKK2 P Rabbit Anti-MEK2 MAPKK2 P Rabbit Anti-MEK2 MAPKK2 P Rabbit Anti-MEK2 MAPKK2 P Rabbit Anti-MEK1 2(MAPKK1 Rabbit Anti-MEK1 2(MAPKK1 Rabbit Anti-MEK1 2(MAPKK1
#26123090 2015/08/24 Save this To Up
Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma.To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy.
1098 related Products with: Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma.Recombinant Human p21 Act Recombinant Polyphosphate Recombinant Polyphosphate Recombinant Polyphosphate Human Serine threonine-pr Native Rabbit Pyruvate Ki p130Cas-associated protei PKA (Protein Kinase A) Ac anti-PKC nu (Protein kina anti-PKC α (Protein kina Rabbit Anti-Mouse Polyplo Mouse Anti-Protein Kinase
#23608443 2013/04/23 Save this To Up
Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach.Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. Although early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death, the latter approaching 70% or more at 5 years. In patients at high risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse-free and overall survival. Neoadjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFN-α. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neoadjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neoadjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFN-α, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab, and BRAF inhibitor vemurafenib) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 and anti-PDL-1) as well as other molecularly targeted agents such as the BRAF inhibitor dabrafenib and the MEK inhibitors trametinib, selumetinib, and MEK162 in the near future. Evaluation of the clinical role of these agents as adjuvant therapy will take years to accomplish to ascertain the relapse-free survival benefits and overall survival benefits of these agents, but neoadjuvant exploration may provide early critical evidence of the therapeutic benefits, as well as clarifying the mechanisms of these agents alone and in combination.
1380 related Products with: Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach.Ofloxacin CAS Number [824 Melanoma; Clone HMB45 Melanoma; Clone HMB45 Melanoma; Clone HMB45 BACTERIOLOGY BACTEROIDES DNA (cytosine 5) methyltr Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge MelanoMax Androgen Receptor (Ab 650
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