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https://www.readbyqxmd.com/read/29610287/advances-on-the-braf-front-in-colorectal-cancer
#1
Filip Janku
<b/> Colorectal cancer with BRAF V600E mutation can be effectively treated with combination approaches involving inhibition of BRAF, MEK, and EGFR proteins. However, activation of the MAPK pathway, often due to emergence of previously undetected molecular alterations, ultimately leads to adaptive therapeutic resistance. Novel combination strategies combining inhibition of BRAF, ERK, and EGFR can be used to prevent MAPK pathway-driven resistance and warrant further investigation. Cancer Discov; 8(4); 389-91...
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29552216/lncrna-bancr-promotes-emt-in-ptc-via-the-raf-mek-erk-signaling-pathway
#2
Yuanyuan Wang, Jiaojiao Gu, Xiangde Lin, Wei Yan, Wenchao Yang, Guoyang Wu
Thyroid cancer is one of the most common types of cancer in the endocrine system. Among all types of thyroid cancer, papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Long non-coding RNA (lncRNA) BRAF-activated non-protein-coding RNA (BANCR) is a 688-bp-long nucleotide transcript, which was first identified in melanoma. The function of BANCR in thyroid cancer remains unclear. The aim of the present study was to investigate whether BANCR is involved in the development of thyroid cancer...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29540830/classifying-braf-alterations-in-cancer-new-rational-therapeutic-strategies-for-actionable-mutations
#3
REVIEW
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
https://www.readbyqxmd.com/read/29525743/mir-296-3p-negatively-regulated-by-nicotine-stimulates-cytoplasmic-translocation-of-c-myc-via-mk2-to-suppress-chemotherapy-resistance
#4
Xiaojie Deng, Zhen Liu, Xiong Liu, Qiaofen Fu, Tongyuan Deng, Juan Lu, Yiyi Liu, Zixi Liang, Qingping Jiang, Chao Cheng, Weiyi Fang
This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop...
February 3, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29507555/the-incidence-and-management-of-cutaneous-adverse-events-of-the-epidermal-growth-factor-receptor-inhibitors
#5
REVIEW
Witold Owczarek, Monika Słowińska, Aleksandra Lesiak, Magdalena Ciążyńska, Aldona Maciąg, Elwira Paluchowska, Luiza Marek-Józefowicz, Rafał Czajkowski
Overexpression of the epidermal growth factor receptor (EGFR) is found in many cancers, including those of the head and neck area, non-small-cell lung cancer, and colorectal, cervical, prostate, breast, ovary, stomach, and pancreatic cancer. The EGFR inhibitors are used at present in the treatment of such cancers. Skin lesions that develop during and after cancer treatment may be due to specific cytostatics, molecular-targeted drugs, radiation therapy, complementary therapy, or the cancer itself, and hence knowledge is essential to distinguish between them...
October 2017: Postȩpy Dermatologii i Alergologii
https://www.readbyqxmd.com/read/29488071/braf-and-mek-inhibitors-use-and-resistance-in-braf-mutated-cancers
#6
Jaquelyn N Sanchez, Ton Wang, Mark S Cohen
The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers...
February 27, 2018: Drugs
https://www.readbyqxmd.com/read/29483217/the-unfolded-protein-response-a-novel-therapeutic-target-for-poor-prognostic-braf-mutant-colorectal-cancer
#7
Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, Sandra Van Schaeybroeck
BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome...
February 26, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29481571/17-aag-inhibits-vemurafenib-associated-map-kinase-activation-and-is-synergistic-with-cellular-immunotherapy-in-a-murine-melanoma-model
#8
Sandeep S Joshi, Shunlin Jiang, Emmanual Unni, Stephen R Goding, Tao Fan, Paul A Antony, Thomas J Hornyak
Heat shock protein 90 (HSP90) is a molecular chaperone which stabilizes client proteins with important roles in tumor growth. 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90 ATPase activity, occupies the ATP binding site of HSP90 causing a conformational change which destabilizes client proteins and directs them towards proteosomal degradation. Malignant melanomas have active RAF-MEK-ERK signaling which can occur either through an activating mutation in BRAF (BRAFV600E) or through activation of signal transduction upstream of BRAF...
2018: PloS One
https://www.readbyqxmd.com/read/29454854/erk1-2-inhibitors-new-weapons-to-inhibit-the-ras-regulated-raf-mek1-2-erk1-2-pathway
#9
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/29431697/convergent-therapeutic-strategies-to-overcome-the-heterogeneity-of-acquired-resistance-in-brafv600e-colorectal-cancer
#10
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
#11
Inna Smalley, Keiran S M Smalley
<b/> 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/29413908/melanoma-metabolism-contributes-to-the-cellular-responses-to-mapk-erk-pathway-inhibitors
#12
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/29363351/mitogen-activated-protein-kinase-mek-inhibitors-to-treat-melanoma-alone-or-in-combination-with-other-kinase-inhibitors
#13
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 30, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29348459/distinct-dependencies-on-receptor-tyrosine-kinases-in-the-regulation-of-mapk-signaling-between-braf-v600e-and-non-v600e-mutant-lung-cancers
#14
Hiroshi Kotani, Yuta Adachi, Hidenori Kitai, Shuta Tomida, Hideaki Bando, Anthony C Faber, Takayuki Yoshino, Dominic C Voon, Seiji Yano, Hiromichi Ebi
BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells...
March 2018: Oncogene
https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#15
Jeffrey J Heard, Ivy Phung, Mark I Potes, Fuyuhiko Tamanoi
BACKGROUND: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29311225/keeping-tumors-out-of-the-mapk-fitness-zone
#16
David F Stern
<b/> Greatest fitness of tumor cell subclones in patients undergoing MAPK-targeting therapies requires just-right levels of MAPK pathway signaling. New therapeutic approaches induce tumor cell death by intensifying MAPK signaling induced by inhibitor withdrawal in combination with DNA damage, or prevent selection of resistant clones with a steep fitness barrier imposed by triple combination of BRAF, MEK, and ERK inhibitors. Cancer Discov; 8(1); 20-3. ©2018 AACR See related article by Hong et al., p. 74 ...
January 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29259016/oncogenic-ras-induced-perinuclear-signaling-complexes-requiring-ksr1-regulate-signal-transmission-to-downstream-targets
#17
Sandip K Basu, Sook Lee, Jacqueline Salotti, Srikanta Basu, Krisada Sakchaisri, Zhen Xiao, Vijay Walia, Christopher J Westlake, Deborah K Morrison, Peter F Johnson
The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here, we show that oncogenic RAS and BRAF induce perinuclear relocalization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α colocalizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29233910/targeting-cdk1-and-mek-erk-overcomes-apoptotic-resistance-in-braf-mutant-human-colorectal-cancer
#18
Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Strebhardt, Kaixiong Tao, Shengbing Huang, Frank A Sinicrope
The BRAF V600E mutation occurs in approximately 8% of human colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAF V600E colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAF V600E colorectal cancer cells. BRAF V600E colorectal cancer cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1, 2, 5, 9 inhibitors)...
March 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29229605/mir-204-5p-and-mir-211-5p-contribute-to-braf-inhibitor-resistance-in-melanoma
#19
Marta Díaz-Martínez, Lucía Benito-Jardón, Lola Alonso, Lisa Koetz-Ploch, Eva Hernando, Joaquin Teixidó
Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29196297/acetylsalicylic-acid-governs-the-effect-of-sorafenib-in-ras-mutant-cancers
#20
Heinz Hammerlindl, Dinoop Ravindran Menon, Sabrina Hammerlindl, Abdullah Al Emran, Joachim Torrano, Katrin Sproesser, Divya Thakkar, Min Xiao, Victoria G Atkinson, Brian Gabrielli, Nikolas K Haass, Meenhard Herlyn, Clemens Krepler, Helmut Schaider
PURPOSE: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult to treat RAS-mutant cancer. EXPERIMENTAL DESIGN: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown...
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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