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Lezi Chen, Quan Chen, Guosan Deng, Wenbin Xie, Jihong Lian, Mian Wang, Huilan Zhu
Recent studies suggest that forced activation of AMP-activated protein kinase (AMPK) could inhibit melanoma cell proliferation. In this report, we evaluated the anti-melanoma cell activity by a novel small-molecular AMPK activator, GSK621. Treatment of GSK621 decreased survival and proliferation of human melanoma cells (A375, WM-115 and SK-Mel-2 lines), which was accompanied by activation of caspase-3/-9 and apoptosis. Reversely, caspase inhibitors attenuated GSK621-induced cytotoxicity against melanoma cells...
October 14, 2016: Biochemical and Biophysical Research Communications
Mark Kerstjens, Emma M C Driessen, Merel Willekes, Sandra S Pinhanços, Pauline Schneider, Rob Pieters, Ronald W Stam
Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro...
August 31, 2016: Oncotarget
Weilong Yao, You-Take Oh, Jiusheng Deng, Ping Yue, Liang Deng, Henry Huang, Wei Zhou, Shi-Yong Sun
Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well-known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism. We found that several MEK inhibitors including MEK162, AZD6244 and PD0325901 effectively decreased DR4 protein levels including cell surface DR4 in different cancer cell lines...
August 30, 2016: Journal of Biological Chemistry
Jinfeng Cao, Renier C Heijkants, Aart G Jochemsen, Mehmet Dogrusöz, Mark J de Lange, Pieter A van der Velden, Sjoerd H van der Burg, Martine J Jager, Robert M Verdijk
PURPOSE: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro. METHODS: 131 conjunctival lesions obtained from 129 patients were collected...
July 22, 2016: Oncotarget
Michael S Lee, Timothy L Helms, Ningping Feng, Jason Gay, Qing Edward Chang, Feng Tian, Ji Y Wu, Carlo Toniatti, Timothy P Heffernan, Garth Powis, Lawrence N Kwong, Scott Kopetz
PURPOSE: 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...
May 4, 2016: Oncotarget
K Watanabe, S Otsu, Y Hirashima, R Morinaga, K Nishikawa, Y Hisamatsu, T Shimokata, M Inada-Inoue, T Shibata, H Takeuchi, T Watanabe, K Tokushige, H Maacke, K Shiaro, Y Ando
PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID)...
June 2016: Cancer Chemotherapy and Pharmacology
Michael K Kiessling, Alessandra Curioni-Fontecedro, Panagiotis Samaras, Silvia Lang, Michael Scharl, Adriano Aguzzi, Derek A Oldrige, John M Maris, Gerhard Rogler
High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines...
2016: PloS One
Daniel H Ahn, Hatice Gulcin Ozer, Baris Hancioglu, Gregory B Lesinski, Cynthia Timmers, Tanios Bekaii-Saab
We previously conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC), where the primary endpoint was response rate. Several patients experienced objective response. These findings were confirmed with MEK162 in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response to selumetinib. Normal and tumor DNA from FFPE tissue from two patients who experienced an objective response underwent whole-exome sequencing...
February 2, 2016: Oncotarget
Michael K Kiessling, Alessandra Curioni-Fontecedro, Panagiotis Samaras, Kirstin Atrott, Jesus Cosin-Roger, Silvia Lang, Michael Scharl, Gerhard Rogler
HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines...
December 8, 2015: Oncotarget
Dipanjan Basu, Cláudia M Salgado, Bruce S Bauer, Donald Johnson, Veronica Rundell, Marina Nikiforova, Yasmin Khakoo, Lorelei J Gunwaldt, Ashok Panigrahy, Miguel Reyes-Múgica
BACKGROUND: Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease. METHODS: We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated...
April 2016: Neuro-oncology
Tuhina Mazumdar, Banibrata Sen, Yifan Wang, Shaohua Peng, Courtney Nicholas, Bonnie S Glisson, Jeffrey N Myers, Faye M Johnson
Treatments for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have limited efficacy. One potential therapeutic target for HNSCC is the RAS/RAF/MEK/ERK cascade, which is one of the major signaling pathways for HNSCC cell survival. In HNSCC, RAS can be activated either by HRAS mutation or by upstream signaling. The ABL inhibitor nilotinib acts as a weak RAF inhibitor that induces RAF dimerization and subsequent activation of MEK/ERK in other cancer cell lines with activated RAS, leading to an unexpected dependence on MEK/ERK for cell survival...
September 2015: Anti-cancer Drugs
Weilong Yao, Ping Yue, Guojing Zhang, Taofeek K Owonikoko, Fadlo R Khuri, Shi-Yong Sun
Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK-targeted therapy. The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis...
August 1, 2015: Cancer Letters
Nadja A Galliker, Carla Murer, Jivko Kamarashev, Reinhard Dummer, Simone M Goldinger
BACKGROUND: Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy. PATIENTS AND METHODS: Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials...
April 2015: European Journal of Dermatology: EJD
Carolina Alquezar, Noemí Esteras, Ana de la Encarnación, Fermín Moreno, Adolfo López de Munain, Ángeles Martín-Requero
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder marked by mild-life onset and progressive changes in behavior, social cognition, and language. Loss-of-function progranulin gene (GRN) mutations are the major cause of FTLD with TDP-43 protein inclusions (FTLD-TDP). Disease-modifying treatments for FTLD-TDP are not available yet. Mounting evidence indicates that cell cycle dysfunction may play a pathogenic role in neurodegenerative disorders including FTLD. Since cell cycle re-entry of posmitotic neurons seems to precede neuronal death, it was hypothesized that strategies aimed at preventing cell cycle progression would have neuroprotective effects...
March 2015: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Leili Ran, Inna Sirota, Zhen Cao, Devan Murphy, Yuedan Chen, Shipra Shukla, Yuanyuan Xie, Michael C Kaufmann, Dong Gao, Sinan Zhu, Ferdinando Rossi, John Wongvipat, Takahiro Taguchi, William D Tap, Ingo K Mellinghoff, Peter Besmer, Cristina R Antonescu, Yu Chen, Ping Chi
UNLABELLED: Gastrointestinal stromal tumor (GIST), originating from the interstitial cells of Cajal (ICC), is characterized by frequent activating mutations of the KIT receptor tyrosine kinase. Despite the clinical success of imatinib, which targets KIT, most patients with advanced GIST develop resistance and eventually die of the disease. The ETS family transcription factor ETV1 is a master regulator of the ICC lineage. Using mouse models of Kit activation and Etv1 ablation, we demonstrate that ETV1 is required for GIST initiation and proliferation in vivo, validating it as a therapeutic target...
March 2015: Cancer Discovery
H Hamidi, M Lu, K Chau, L Anderson, M Fejzo, C Ginther, R Linnartz, A Zubel, D J Slamon, R S Finn
BACKGROUND: To study the molecular mechanism regulating sensitivity to MEK inhibition in pancreatic cancer cell lines. METHODS: A growth inhibition assay determined sensitivity to MEK162 in a panel of 29 pancreatic cancer cell lines. For the same panel, KRAS mutational status and copy-number variation (CNV) was determine using PCR, array CGH and FISH. Two sensitive and two resistant cell lines were further interrogated for difference in baseline and MEK162-induced gene expression, as well as signal transduction using microarray and western blotting...
October 28, 2014: British Journal of Cancer
Vito W Rebecca, Gretchen M Alicea, Kim H T Paraiso, Harshani Lawrence, Geoffrey T Gibney, Keiran S M Smalley
The MEK inhibitor MEK162 is the first targeted therapy agent with clinical activity in patients whose melanomas harbor NRAS mutations; however, median PFS is 3.7 months, suggesting the rapid onset of resistance in the majority of patients. Here, we show that treatment of NRAS-mutant melanoma cell lines with the MEK inhibitors AZD6244 or trametinib resulted in a rebound activation of phospho-ERK (pERK). Functionally, the recovery of signaling was associated with the maintenance of cyclin-D1 expression and therapeutic escape...
November 2014: Pigment Cell & Melanoma Research
U Urner-Bloch, M Urner, P Stieger, N Galliker, N Winterton, A Zubel, L Moutouh-de Parseval, R Dummer, S M Goldinger
BACKGROUND: Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes. PATIENTS AND METHODS: Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials...
July 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Jaykumar Thumar, David Shahbazian, Saadia A Aziz, Lucia B Jilaveanu, Harriet M Kluger
BACKGROUND: Gain of function mutations in B-RAF and N-RAS occur frequently in melanoma, leading to mitogen activating protein kinase (MAPK) pathway activation, and this pathway is the target of drugs in development. Our purpose was to study clinical characteristics of patients with mutations in this pathway and to determine activity of inhibitors of B-RAF and MEK in short term cultures grown from tumors of some of these patients. METHODS: Clinical and pathologic data were collected retrospectively on melanoma patients tested for B-RAF and N-RAS mutations at the Yale Cancer Center and associations with survival were determined...
2014: Molecular Cancer
Kira Gritsman, Haluk Yuzugullu, Thanh Von, Howard Yan, Linda Clayton, Christine Fritsch, Sauveur-Michel Maira, Gregory Hollingworth, Christine Choi, Tulasi Khandan, Mahnaz Paktinat, Rachel O Okabe, Thomas M Roberts, Jean J Zhao
The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system...
April 2014: Journal of Clinical Investigation
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