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https://www.readbyqxmd.com/read/29437705/nras-mutated-rhabdomyosarcoma-cells-are-vulnerable-to-mitochondrial-apoptosis-induced-by-co-inhibition-of-mek-and-pi3k%C3%AE
#1
Nadezda Dolgikh, Manuela Hugle, Meike Vogler, Simone Fulda
Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here we report that co-inhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wildtype, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wildtype RMS tumors in vivo...
February 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29137241/erk-inhibition-sensitizes-cz415-induced-anti-osteosarcoma-activity-in-vitro-and-in-vivo
#2
Gang Yin, Jin Fan, Wei Zhou, Qingfeng Ding, Jun Zhang, Xuan Wu, Pengyu Tang, Hao Zhou, Bowen Wan, Guoyong Yin
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29024814/anti-tumor-effects-of-nvp-bkm120-alone-or-in-combination-with-mek162-in-biliary-tract-cancer
#3
Ling Jin, Mei-Hua Jin, Ah-Rong Nam, Ji-Eun Park, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang
There are currently no clinically validated therapeutic targets for biliary tract cancer (BTC). Despite promising results in other cancers, compounds targeting the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, alone or in combination with Ras/Raf/MEK pathway inhibitors, have not been evaluated in BTC. Here, we examined the effects of a pan-PI3K inhibitor (BKM120) with or without a MEK inhibitor (MEK162), on eight human BTC cell lines carrying mutations in K-Ras and/or the PI3K catalytic subunit, PI3KCA...
December 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28958992/identification-of-mek162-as-a-radiosensitizer-for-the-treatment-of-glioblastoma
#4
Ravi S Narayan, Ana Gasol, Paul L G Slangen, Fleur M G Cornelissen, Tonny Lagerweij, Hou Y Y E Veldman, Rogier Dik, Jaap van den Berg, Ben J Slotman, Thomas Wurdinger, Daphne Haas-Kogan, Lukas J A Stalpers, Brigitta G Baumert, Bart Westerman, Jan Theys, Peter Sminia
Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied pre-clinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small molecule drugs including MK2206, RAD001, BEZ235, MLN0128 and MEK162, alone and in combination with irradiation...
September 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28938534/targeting-of-the-mapk-and-akt-pathways-in-conjunctival-melanoma-shows-potential-synergy
#5
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...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28921565/the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-pharmacokinetics-and-pharmacodynamics-of-a-panel-of-mek-inhibitors
#6
Mark C de Gooijer, Ping Zhang, Ruud Weijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain...
January 15, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28919996/mek-inhibition-and-immune-responses-in-advanced-melanoma
#7
REVIEW
Reinhard Dummer, Egle Ramelyte, Sabrina Schindler, Olaf Thürigen, Mitchell P Levesque, Peter Koelblinger
phase II and III clinical trials demonstrated modest anti- tumor activity of Binimetinib (MEK162) - a potent allosteric inhibitor of MEK1 and MEK2- in patients with advanced NRAS mutant melanoma. The analysis of the NEMO study in NRAS mutated melanoma, has shown that pre-treatment with immunotherapy improved the outcome of binimetinib therapy. We discuss this finding in the context of in vitro and in vivo effects of MEK inhibition on immuno-critical pathways and interactions.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28611306/erk-inhibition-sensitizes-cz415-induced-anti-osteosarcoma-activity-in-vitro-and-in-vivo
#8
Gang Yin, Jin Fan, Wei Zhou, Qingfeng Ding, Jun Zhang, Xuan Wu, Pengyu Tang, Hao Zhou, Bowen Wan, Guoyong Yin
mTOR is a valuable oncotarget for osteosarcoma. The anti-osteosarcoma activity by a novel mTOR kinase inhibitor, CZ415, was evaluated. We demonstrated that CZ415 potently inhibited survival and proliferation of known osteosarcoma cell lines (U2OS, MG-63 and SaOs2), and primary human osteosarcoma cells. Further, CZ415 provoked apoptosis and disrupted cell cycle progression in osteosarcoma cells. CZ415 treatment in osteosarcoma cells concurrently blocked mTORC1 and mTORC2 activation. Intriguingly, ERK-MAPK activation could be a major resistance factor of CZ415...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28551618/mek162-enhances-antitumor-activity-of-5-fluorouracil-and-trifluridine-in-kras-mutated-human-colorectal-cancer-cell-lines
#9
Jun Gong, Yuan Chen, Lixin Yang, Raju Pillai, Senji Shirasawa, Marwan Fakih
BACKGROUND: Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy...
June 2017: Anticancer Research
https://www.readbyqxmd.com/read/28496202/inhibition-of-jak-stat-signaling-reduces-the-activation-of-pancreatic-stellate-cells-in-vitro-and-limits-caerulein-induced-chronic-pancreatitis-in-vivo
#10
Hannah M Komar, Gregory Serpa, Claire Kerscher, Erin Schwoegl, Thomas A Mace, Ming Jin, Ming-Chen Yang, Ching-Shih Chen, Mark Bloomston, Michael C Ostrowski, Phil A Hart, Darwin L Conwell, Gregory B Lesinski
Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28404914/the-preclinical-assessment-of-xl388-a-mtor-kinase-inhibitor-as-a-promising-anti-renal-cell-carcinoma-agent
#11
Zuquan Xiong, Yiwen Zang, Shan Zhong, Lujia Zou, Yishuo Wu, Shenghua Liu, Zujun Fang, Zhoujun Shen, Qiang Ding, Shanwen Chen
XL388 is a mammalian target of rapamycin (mTOR) kinase inhibitor. We demonstrated that XL388 inhibited survival and proliferation of renal cell carcinoma (RCC) cell lines (786-0 and A549) and primary human RCC cells. XL388 activated caspase-dependent apoptosis in the RCC cells. XL388 blocked mTOR complex 1 (mTORC1) and mTORC2 activation, and depleted hypoxia-inducible factor 1α (HIF1α) and HIF-2α expression in RCC cells. Yet, XL388 was ineffective in RCC cells with mTOR shRNA knockdown or kinase-dead mutation...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28248226/activity-based-proteomics-reveals-heterogeneous-kinome-and-atp-binding-proteome-responses-to-mek-inhibition-in-kras-mutant-lung-cancer
#12
Jae-Young Kim, Paul A Stewart, Adam L Borne, Bin Fang, Eric A Welsh, Yian Ann Chen, Steven A Eschrich, John M Koomen, Eric B Haura
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS...
April 27, 2016: Proteomes
https://www.readbyqxmd.com/read/28154798/activity-based-proteomics-reveals-heterogeneous-kinome-and-atp-binding-proteome-responses-to-mek-inhibition-in-kras-mutant-lung-cancer
#13
Jae-Young Kim, Paul A Stewart, Adam L Borne, Bin Fang, Eric A Welsh, Yian Ann Chen, Steven A Eschrich, John M Koomen, Eric B Haura
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS...
June 2016: Proteomes
https://www.readbyqxmd.com/read/28152546/a-phase-1-dose-escalation-and-expansion-study-of-binimetinib-mek162-a-potent-and-selective-oral-mek1-2-inhibitor
#14
MULTICENTER STUDY
Johanna C Bendell, Milind Javle, Tanios S Bekaii-Saab, Richard S Finn, Zev A Wainberg, Daniel A Laheru, Colin D Weekes, Benjamin R Tan, Gazala N Khan, Mark M Zalupski, Jeffrey R Infante, Suzanne Jones, Kyriakos P Papadopoulos, Anthony W Tolcher, Renae E Chavira, Janna L Christy-Bittel, Emma Barrett, Amita Patnaik
BACKGROUND: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. METHODS: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design...
February 28, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/27811010/dual-inhibition-of-mek-and-pi3k-akt-rescues-cancer-cachexia-through-both-tumor-extrinsic-and-intrinsic-activities
#15
Erin E Talbert, Jennifer Yang, Thomas A Mace, Matthew R Farren, Alton B Farris, Gregory S Young, Omar Elnaggar, Zheng Che, Cynthia D Timmers, Priyani Rajasekera, Jennifer M Maskarinec, Mark Bloomston, Tanios Bekaii-Saab, Denis C Guttridge, Gregory B Lesinski
Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162...
February 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27793696/baseline-mapk-signaling-activity-confers-intrinsic-radioresistance-to-kras-mutant-colorectal-carcinoma-cells-by-rapid-upregulation-of-heterogeneous-nuclear-ribonucleoprotein-k-hnrnp-k
#16
Stefan Eder, Annette Arndt, Andreas Lamkowski, Wassiliki Daskalaki, Alexis Rump, Markus Priller, Felicitas Genze, Eva Wardelmann, Matthias Port, Konrad Steinestel
Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is overexpressed in malignant tumors and involved in DNA damage response upon ionizing radiation (IR). Here, we investigate its role in radioresistance of colorectal carcinoma (CRC) and evaluate a pharmacological approach to enhance CRC radiosensitivity via downregulation of hnRNP K. We show that hnRNP K is overexpressed in CRC tissue specimens and upregulated in response to IR in vitro, which occurs faster in KRAS-mutant CRC cells. HnRNP K knockdown impairs cell survival, cell cycle progression and KRAS-dependent radioresistance and increases apoptosis...
January 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27751856/ampk-activation-by-gsk621-inhibits-human-melanoma-cells-in%C3%A2-vitro-and-in%C3%A2-vivo
#17
Lezi Chen, Quan Chen, Guosan Deng, Shifeng Kuang, 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...
November 25, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27588400/mek-inhibition-is-a-promising-therapeutic-strategy-for-mll-rearranged-infant-acute-lymphoblastic-leukemia-patients-carrying-ras-mutations
#18
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...
February 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/27576686/expression-of-death-receptor-4-is-positively-regulated-by-mek-erk-ap-1-signaling-and-suppressed-upon-mek-inhibition
#19
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...
October 7, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27462917/targeting-of-the-mapk-and-akt-pathways-in-conjunctival-melanoma-shows-potential-synergy
#20
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
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