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https://www.readbyqxmd.com/read/29454854/erk1-2-inhibitors-new-weapons-to-inhibit-the-ras-regulated-raf-mek1-2-erk1-2-pathway
#1
REVIEW
Andrew M Kidger, James Sipthorp, Simon J Cook
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons...
February 15, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29454849/escmid-study-group-for-infections-in-compromised-hosts-esgich-consensus-document-on-the-safety-of-targeted-and-biological-therapies-an-infectious-diseases-perspective-intracellular-signaling-pathways-tyrosine-kinase-and-mtor-inhibitors
#2
REVIEW
Mark Reinwald, Jose T Silva, Nicolas J Mueller, Jesús Fortún, Christian Garzoni, Johan W de Fijter, Mario Fernández-Ruiz, Paolo Grossi, Jose María Aguado
BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family...
February 15, 2018: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29440321/targeting-the-mapk-pathway-in-ras-mutant-cancers
#3
Sarah G Hymowitz, Shiva Malek
Despite decades of extensive drug discovery efforts, there are currently no targeted therapies approved to treat KRAS mutant cancers. In this review, we highlight the challenges and opportunities in targeting KRAS mutant tumors through inhibition of mitogen-activated protein kinase (MAPK) signaling with conformation-specific kinase inhibitors. Through structural analysis and mechanistic studies with BRAF and mitogen-activated protein kinase (MEK) inhibitors, we describe how kinase-dependent and -independent functions of MAPK signaling components regulate KRAS-driven tumorigenesis and how these insights can be used to treat RAS mutant cancers with small molecule kinase inhibitors...
February 12, 2018: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29435119/a-dual-mechanism-of-activation-of-the-sonic-hedgehog-pathway-in-anaplastic-thyroid-cancer-crosstalk-with-ras-braf-mek-pathway-and-ligand-secretion-by-tumor-stroma
#4
Alessia Parascandolo, Mikko O Laukkanen, Nancy De Rosa, Clara Ugolini, Maria Carmela Cantisani, Anna Maria Cirafici, Fulvio Basolo, Massimo Santoro, Maria Domenica Castellone
Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29433126/mek-drives-braf-activation-through-allosteric-control-of-ksr-proteins
#5
Hugo Lavoie, Malha Sahmi, Pierre Maisonneuve, Sara A Marullo, Neroshan Thevakumaran, Ting Jin, Igor Kurinov, Frank Sicheri, Marc Therrien
RAF family kinases have prominent roles in cancer. Their activation is dependent on dimerization of their kinase domains, which has emerged as a hindrance for drug development. In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically...
February 12, 2018: Nature
https://www.readbyqxmd.com/read/29431699/combined-braf-egfr-and-mek-inhibition-in-patients-with-brafv600e-mutant-colorectal-cancer
#6
Ryan B Corcoran, Thierry Andre, Chloe E Atreya, Jan H M Schellens, Takayuki Yoshino, Johanna C Bendell, Antoine Hollebecque, Autumn J McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S Gordon, Josep Tabernero, Rona Yaeger, Peter J O'Dwyer, Yves Humblet, Filip De Vos, A Scott Jung, Jan C Brase, Savina Jaeger, Severine Bettinger, Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only ~5% with BRAFV600E colorectal cancer (CRC) respond. Preclinical studies suggest that lack of efficacy in BRAFV600E CRC is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E CRC...
February 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29431697/convergent-therapeutic-strategies-to-overcome-the-heterogeneity-of-acquired-resistance-in-brafv600e-colorectal-cancer
#7
Mehlika Hazar-Rethinam, Marianna Kleyman, G Celine Han, David Liu, Leanne G Ahronian, Heather A Shahzade, Lifeng Chen, Aparna R Parikh, Jill N Allen, Jeffrey W Clark, Eunice L Kwak, Jason E Faris, Janet E Murphy, Theodore S Hong, Emily E Van Seventer, Brandon Nadres, Catriona B Hong, Joseph M Gurski, Nicholas A Jessop, Dora Dias-Santagata, A John Iafrate, Eliezer M Van Allen, Ryan B Corcoran
Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from BRAFV600E colorectal cancer patients receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a novel pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo...
February 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29431672/erk-inhibition-a-new-front-in-the-war-against-mapk-pathway-driven-cancers
#8
Inna Smalley, Keiran S M Smalley
ERK inhibitors have enormous therapeutic potential against tumors that are BRAF mutant, BRAF-MEK inhibitor resistant, or RAS mutant. In this issue of Cancer Discovery, Sullivan and colleagues report on the first-in-human dose-escalation study of the ERK inhibitor ulixertinib, which they show to be well tolerated with clinical activity against a wide range of tumor types. Cancer Discov; 8(2); 140-2. ©2018 AACR.See related article by Sullivan et al., p. 184.
February 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29423085/the-anti-rheumatic-drug-leflunomide-synergizes-with-mek-inhibition-to-suppress-melanoma-growth
#9
Kimberley Hanson, Stephen R Robinson, Karamallah Al-Yousuf, Adam E Hendry, Darren W Sexton, Victoria Sherwood, Grant N Wheeler
Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29417399/melanoma-brain-metastases-local-therapies-targeted-therapies-immune-checkpoint-inhibitors-and-their-combinations-chances-and-challenges
#10
REVIEW
Marvin Kuske, Ricarda Rauschenberg, Marlene Garzarolli, Michelle Meredyth-Stewart, Stefan Beissert, Esther G C Troost, Oliva Isabella Claudia Glitza, Friedegund Meier
Recent phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are active in patients with melanoma brain metastases (MBM), reporting intracranial disease control rates of 50-75%. Furthermore, retrospective analyses suggest that combining stereotactic radiosurgery with immune checkpoint inhibitors or BRAF/MEK inhibitors prolongs overall survival. These data stress the need for inter- and multidisciplinary cooperation that takes into account the individual prognostic factors in order to establish the best treatment for each patient...
February 7, 2018: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/29413908/melanoma-metabolism-contributes-to-the-cellular-responses-to-mapk-erk-pathway-inhibitors
#11
REVIEW
Philippe Marchetti, Anne Trinh, Raeeka Khamari, Jerome Kluza
BACKGROUND: Besides its influence on survival, growth, proliferation, invasion and metastasis, cancer cell metabolism also greatly influences the cellular responses to molecular-targeted therapies. SCOPE OF THE REVIEW: To review the recent advances in elucidating the metabolic effects of BRAF and MEK inhibitors (clinical inhibitors of the MAPK/ERK pathway) in melanoma and discuss the underlying mechanisms involved in the way metabolism can influence melanoma cell death and resistance to BRAF and MEK inhibitors...
January 31, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29405038/systemic-treatments-for-metastatic-cutaneous-melanoma
#12
REVIEW
Sandro Pasquali, Andreas V Hadjinicolaou, Vanna Chiarion Sileni, Carlo Riccardo Rossi, Simone Mocellin
BACKGROUND: The prognosis of people with metastatic cutaneous melanoma, a skin cancer, is generally poor. Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small-molecule targeted drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. This is an update of a Cochrane Review published in 2000. OBJECTIVES: To assess the beneficial and harmful effects of systemic treatments for metastatic cutaneous melanoma...
February 6, 2018: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/29399330/recent-advances-in-managing-differentiated-thyroid-cancer
#13
REVIEW
Livia Lamartina, Giorgio Grani, Cosimo Durante, Sebastiano Filetti
The main clinical challenge in the management of thyroid cancer is to avoid over-treatment and over-diagnosis in patients with lower-risk disease while promptly identifying those patients with more advanced or high-risk disease requiring aggressive treatment. In recent years, novel clinical and molecular data have emerged, allowing the development of new staging systems, predictive and prognostic tools, and treatment approaches. There has been a notable shift toward more conservative management of low- and intermediate-risk patients, characterized by less extensive surgery, more selective use of radioisotopes (for both diagnostic and therapeutic purposes), and less intensive follow-up...
2018: F1000Research
https://www.readbyqxmd.com/read/29389895/ovarian-cancers-genetic-abnormalities-tumor-heterogeneity-and-progression-clonal-evolution-and-cancer-stem-cells
#14
REVIEW
Ugo Testa, Eleonora Petrucci, Luca Pasquini, Germana Castelli, Elvira Pelosi
Four main histological subtypes of ovarian cancer exist: serous (the most frequent), endometrioid, mucinous and clear cell; in each subtype, low and high grade. The large majority of ovarian cancers are diagnosed as high-grade serous ovarian cancers (HGS-OvCas). TP53 is the most frequently mutated gene in HGS-OvCas; about 50% of these tumors displayed defective homologous recombination due to germline and somatic BRCA mutations, epigenetic inactivation of BRCA and abnormalities of DNA repair genes; somatic copy number alterations are frequent in these tumors and some of them are associated with prognosis; defective NOTCH, RAS/MEK, PI3K and FOXM1 pathway signaling is frequent...
February 1, 2018: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/29388014/the-landscape-of-genetic-alterations-in-ameloblastomas-relates-to-clinical-features
#15
Sibel Elif Gültekin, Reem Aziz, Carina Heydt, Burcu Sengüven, Joachim Zöller, Ali Farid Safi, Matthias Kreppel, Reinhard Buettner
Ameloblastoma is a mostly benign, but locally invasive odontogenic tumor eliciting frequent relapses and significant morbidity. Recently, mutually exclusive mutations in BRAF and SMO were identified causing constitutive activation of MAPK and hedgehog signaling pathways. To explore further such clinically relevant genotype-phenotype correlations, we here comprehensively analyzed a large series of ameloblastomas (98 paraffin block of 76 patients) with respect to genomic alterations, clinical presentation, and histological features collected from the archives of three different pathology centers in France, Germany, and Turkey...
February 1, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29387762/multiple-epidermotropic-melanoma-metastases-developing-during-braf-and-mek-inhibitor-therapy
#16
Raphael Reinhard, Christoffer Gebhardt, Nolwenn Maurier, Lionel Larribère, Azadeh Orouji, Jochen Utikal
No abstract text is available yet for this article.
March 2018: JAAD Case Reports
https://www.readbyqxmd.com/read/29380516/response-to-the-braf-mek-inhibitors-dabrafenib-trametinib-in-an-adolescent-with-a-braf-v600e-mutated-anaplastic-ganglioglioma-intolerant-to-vemurafenib
#17
Asher M Marks, Ranjit S Bindra, Michael L DiLuna, Anita Huttner, Vikram Jairam, Kristopher T Kahle, Mark W Kieran
Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction...
January 30, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29369501/targeted-therapy-for-infants-with-diencephalic-syndrome-a-case-report-and-review-of-management-strategies
#18
Lars M Wagner, John S Myseros, Douglas E Lukins, Christi M Willen, Roger J Packer
Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine...
January 25, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29369405/targeting-insulin-like-growth-factor-2-mrna-binding-protein-1-igf2bp1-in-metastatic-melanoma-to-increase-efficacy-of-brafv600e-inhibitors
#19
Tae Won Kim, Thomas Havighurst, KyungMann Kim, Mark Albertini, Yaohui G Xu, Vladimir S Spiegelman
Melanoma is one of the deadliest forms of skin cancer. Although BRAF inhibitors significantly enhance survival of metastatic melanoma patients, most patients relapse after less than a year of treatment. We previously reported that mRNA binding protein Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is overexpressed in metastatic melanoma and that expression of IGF2BP1 confers resistance to chemotherapeutic agents. Here we demonstrate that IGF2BP1 plays an important role in the sensitivity of melanoma to targeted therapy...
January 25, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29363351/mitogen-activated-protein-kinase-mek-inhibitors-to-treat-melanoma-alone-or-in-combination-with-other-kinase-inhibitors
#20
Elnaz Faghfuri, Shekoufeh Nikfar, Kamal Niaz, Mohammad Ali Faramarzi, Mohammad Abdollahi
Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower toxicity and improved overall survival versus conventional therapies of MM. The revealing of mutations in the BRAF/MEK/ERK pathway has led to the development of BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of cutaneous MM. Though, progression of resistance to these agents has prompted attempts to target downstream proteins in this pathway...
January 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
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