keyword
https://read.qxmd.com/read/38493021/preclinical-efficacy-of-raf-mek-clamp-avutometinib-in-combination-with-fak-inhibition-in-low-grade-serous-ovarian-cancer
#1
JOURNAL ARTICLE
Blair McNamara, Cem Demirkiran, Tobias Max Philipp Hartwich, Stefania Bellone, Diego Manavella, Levent Mutlu, Michelle Greenman, Margherita Zipponi, Yang Yang-Hartwich, Kevin Yang, Elena Ratner, Peter E Schwartz, Silvia Coma, Jonathan A Pachter, Alessandro D Santin
OBJECTIVES: Low-grade-serous-ovarian-carcinoma (LGSOC) is characterized by a high recurrence rate and limited therapeutic options. About one-third of LGSOC contains mutations in MAPK pathway genes such as KRAS/NRAS/BRAF. Avutometinib is a dual RAF/MEK inhibitor while defactinib and VS-4718 are focal-adhesion-kinase-inhibitors (FAKi). We determined the preclinical efficacy of avutometinib±VS-4718 in LGSOC patient-derived-tumor-xenografts (PDX). METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic fingerprint of 3 patient-derived LGSOC (OVA(K)250, PERIT(M)17 and A(PE)148)...
February 9, 2024: Gynecologic Oncology
https://read.qxmd.com/read/38473413/pancreatic-cancer-treatment-targeting-the-hgf-c-met-pathway-the-mek-inhibitor-trametinib
#2
REVIEW
Junyeol Kim, Tae Seung Lee, Myeong Hwan Lee, In Rae Cho, Ji Kon Ryu, Yong-Tae Kim, Sang Hyub Lee, Woo Hyun Paik
Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors...
March 5, 2024: Cancers
https://read.qxmd.com/read/38472669/variant-analysis-of-mirna-regulatory-genes-in-35-sporadic-lung-carcinoma-tumors
#3
JOURNAL ARTICLE
Özkan Bağcı, Ebru Marzioğlu Özdemir, Batuhan Şanlıtürk
UNLABELLED: Lung cancer is one of the cancer types with the highest mortality worldwide. The most frequently mutated genes known to be clinically important in lung cancers are EGFR, BRAF, and KRAS genes. Therefore, the therapeutic agents developed are directed against variants that cause over-activation of the EGFR-KRAS-BRAF-BRAF-MEK/ERK signalling pathway. However, different responses of patients to Tyrosine Kinase Inhibitors (TKIs) suggest that new prognostic biomarkers should be defined and epigenetic mechanisms may be related to this situation...
March 12, 2024: Doklady. Biochemistry and Biophysics
https://read.qxmd.com/read/38388830/the-cnk-hyp-scaffolding-complex-promotes-raf-activation-by-enhancing-ksr-mek-interaction
#4
JOURNAL ARTICLE
Pierre Maisonneuve, Malha Sahmi, Fanny Bergeron-Labrecque, Xianjie Iris Ma, Juliette Queguiner, Geneviève Arseneault, Martin Lefrançois, Igor Kurinov, Rémi Fronzes, Frank Sicheri, Marc Therrien
The RAS-MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains only partially understood. There are three RAF isoforms in mammals (ARAF, BRAF and CRAF) and two related pseudokinases (KSR1 and KSR2). RAS-mediated activation of RAF depends on an allosteric mechanism driven by the dimerization of its kinase domain...
February 22, 2024: Nature Structural & Molecular Biology
https://read.qxmd.com/read/38341356/targeting-mek-in-non-small-cell-lung-cancer
#5
JOURNAL ARTICLE
Matthew S Lara, Collin M Blakely, Jonathan W Riess
The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR, activating mutations in MEK are exceedingly rare in NSCLC. Instead, enhanced activation of the MEK pathway is often linked to increased signaling by upstream oncogenic driver mutations. Thus far, MEK inhibitor monotherapy has shown little promise. However, treatment strategies involving MEK inhibition in combination with other targeted therapies in other oncogene-driven NSCLC has proven to be encouraging...
February 9, 2024: Current Problems in Cancer
https://read.qxmd.com/read/38291372/loggic-firefly-2-a-phase-3-randomized-trial-of-tovorafenib-vs-chemotherapy-in-pediatric-and-young-adult-patients-with-newly-diagnosed-low-grade-glioma-harboring-an-activating-raf-alteration
#6
RANDOMIZED CONTROLLED TRIAL
Cornelis M van Tilburg, Lindsay B Kilburn, Sébastien Perreault, Rene Schmidt, Amedeo A Azizi, Ofelia Cruz-Martínez, Michal Zápotocký, Katrin Scheinemann, Antoinette Y N Schouten-van Meeteren, Astrid Sehested, Enrico Opocher, Pablo Hernáiz Driever, Shivaram Avula, David S Ziegler, David Capper, Arend Koch, Felix Sahm, Jiaheng Qiu, Li-Pen Tsao, Samuel C Blackman, Peter Manley, Till Milde, Ruth Witt, David T W Jones, Darren Hargrave, Olaf Witt
BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG...
January 30, 2024: BMC Cancer
https://read.qxmd.com/read/38203795/molecular-targeting-of-the-braf-proto-oncogene-mitogen-activated-protein-kinase-mapk-pathway-across-cancers
#7
REVIEW
Khine S Shan, Tauseef U Rehman, Stan Ivanov, Gelenis Domingo, Luis E Raez
The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations...
January 3, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38183801/vaccine-antibodies-against-a-synthetic-epidermal-growth-factor-variant-enhance-the-antitumor-effects-of-inhibitors-targeting-the-mapk-erk-and-pi3k-akt-pathways
#8
JOURNAL ARTICLE
Silvia García-Roman, Mónica Garzón-Ibáñez, Jordi Bertrán-Alamillo, Núria Jordana-Ariza, Ana Giménez-Capitán, Beatriz García-Peláez, Marta Vives-Usano, Jordi Codony-Servat, Erik d'Hondt, Rafael Rosell, Miguel Ángel Molina-Vila
BACKGROUND: The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) could potentiate the activity of drugs targeting the ERK/MAPK and PI3K/Akt pathways. METHODS: Non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma cell lines harboring KRAS, NRAS, BRAF and PIK3CA mutations were used...
January 5, 2024: Translational Oncology
https://read.qxmd.com/read/38086758/concomitant-non-v600e-braf-and-kras-mutations-in-colorectal-carcinoma-by-next-generation-sequencing-a-distinct-subtype
#9
JOURNAL ARTICLE
Pallavi Srivastava, Sridhar Mishra, Saumya Shukla, Pooja Sharma, Nuzhat Husain
The RAS-RAF-MEK-ERK signaling cascade is the most frequently affected signaling pathway in colorectal cancer. BRAFV600E mutations serve as a drug-treatable hotspot and KRAS mutations as a predictor of susceptibility to anti-epidermal growth factor receptor therapy. Concomitant non-V600E BRAF and KRAS mutations may coexist and are rarely reported in the literature. We report a patient of colorectal carcinoma with inguinal lymph node metastases harboring mutations at the KRAS and BRAF non-V600E mutation codon detected by next-generation sequencing with an emphasis on clinical, pathological, and therapeutic implications of the mutation and review of the literature...
December 12, 2023: International Journal of Surgical Pathology
https://read.qxmd.com/read/38074649/case-report-balancing-immune-responses-multiple-sclerosis-disease-exacerbation-under-braf-mek-treatment-for-malignant-melanoma
#10
Katrin Pape, Maria Protopapa, Muriel Schraad, Falk Steffen, Frauke Zipp, Stefan Bittner
BACKGROUND: Combination treatment with BRAF/MEK inhibitors favorably impact progression-free survival in malignant melanoma. However, it may cause paradoxical activation of the MAPK/ERK pathway in immune cells without BRAF mutation, which may lead to over activation of the immune system, especially in patients with pre-existing autoimmune conditions. In this case report, treatment of malignant melanoma with BRAF/MEK inhibitors was associated with radiological disease exacerbation of pre-existing multiple sclerosis (MS)...
2023: Frontiers in Oncology
https://read.qxmd.com/read/38067230/exploring-the-in-vitro-and-in-vivo-therapeutic-potential-of-braf-and-mek-inhibitor-combination-in-nras-mutated-melanoma
#11
JOURNAL ARTICLE
Heike Niessner, Anna Hüsch, Corinna Kosnopfel, Matthias Meinhardt, Dana Westphal, Friedegund Meier, Bastian Schilling, Tobias Sinnberg
INTRODUCTION: Patients with NRAS-mutant metastatic melanoma often have an aggressive disease requiring a fast-acting, effective therapy. The MEK inhibitor binimetinib shows an overall response rate of 15% in patients with NRAS-mutant melanoma, providing a backbone for combination strategies. Our previous studies demonstrated that in NRAS-mutant melanoma, the antitumor activity of the MEK inhibitor binimetinib was significantly potentiated by the BRAFV600E/K inhibitor encorafenib through the induction of ER stress, leading to melanoma cell death by apoptotic mechanisms...
November 22, 2023: Cancers
https://read.qxmd.com/read/38052158/activation-of-mitogen-activated-protein-kinase-signaling-and-development-of-papillary-thyroid-carcinoma-in-thyroid-stimulating-hormone-receptor-d633h-knockin-mice
#12
JOURNAL ARTICLE
Markus Eszlinger, Alexandra Stephenson, Shideh Mirhadi, Konrad Patyra, Michael F Moran, Moosa Khalil, Jukka Kero, Ralf Paschke
OBJECTIVE: Nonautoimmune hyperthyroidism (NAH) is rare and occurs due to a constitutively activating thyroid stimulating hormone receptor (TSHR) mutation. In contrast to other thyroid nodules, no further evaluation for malignancy is recommended for hot thyroid nodules. In the first model for NAH in mice nearly all homozygous mice had developed papillary thyroid cancer by 12 months of age. METHODS: To further evaluate these mice, whole exome sequencing and phosphoproteome analysis were employed in a further generation of mice to identify any other mutations potentially responsible and to identify the pathways involved in thyroid carcinoma development...
December 1, 2023: European Thyroid Journal
https://read.qxmd.com/read/38021761/the-role-of-braf-inhibitors-in-the-management-of-ameloblastoma-a-literature-review
#13
REVIEW
Arindam Malakar, V Raj Kumar, Priya Yadav, Vishal Bhardwaj, Chuimee Gogoi Barua, Gourika Bhardwaj
Ameloblastoma is one of the most prevalent but enigmatic benign odontogenic tumors of the jaw, accounting for approximately 10% of all maxillary and mandibular tumors. This neoplasia is distinguished by exhibiting several clinical and histological variants along with several mutations that affect its behavior. The ameloblastoma treatment plan is determined by the tumor's size, anatomical location, histologic variant, and anatomical involvement. On chromosome 7, there is a proto-oncogene called BRAF. When BRAF is mutated, it becomes an oncogene and continuously produces proteins like MEK and ERK, members of mitogen-activated protein kinase (MAPK)...
October 2023: Curēus
https://read.qxmd.com/read/38014104/ksr1-knockout-mouse-model-demonstrates-mapk-pathway-s-key-role-in-cisplatin-and-noise-induced-hearing-loss
#14
Matthew A Ingersoll, Richard D Lutze, Regina G Kelmann, Daniel F Kresock, Jordan D Marsh, Rene V Quevedo, Jian Zuo, Tal Teitz
UNLABELLED: Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise- induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells...
November 13, 2023: bioRxiv
https://read.qxmd.com/read/37972012/p53-armed-oncolytic-adenovirus-induces-autophagy-and-apoptosis-in-kras-and-braf-mutant-colorectal-cancer-cells
#15
JOURNAL ARTICLE
Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Yuncheng Li, Motohiko Yamada, Satoru Kikuchi, Shinji Kuroda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara
Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells...
2023: PloS One
https://read.qxmd.com/read/37920504/multi-omics-reveals-aging-related-pathway-in-natural-aging-mouse-liver
#16
JOURNAL ARTICLE
Cong-Min Tang, Zhen Zhang, Yan Sun, Wen-Jing Ding, Xue-Chun Yang, Yi-Ping Song, Ming-Ying Ling, Xue-Hui Li, Rong Yan, Yu-Jing Zheng, Na Yu, Wen-Hua Zhang, Yong Wang, Shao-Peng Wang, Hai-Qing Gao, Chuan-Li Zhao, Yan-Qiu Xing
Aging is associated with gradual changes in liver structure, altered metabolites and other physiological/pathological functions in hepatic cells. However, its characterized phenotypes based on altered metabolites and the underlying biological mechanism are unclear. Advancements in high-throughput omics technology provide new opportunities to understand the pathological process of aging. Here, in our present study, both metabolomics and phosphoproteomics were applied to identify the altered metabolites and phosphorylated proteins in liver of young (the WTY group) and naturally aged (the WTA group) mice, to find novel biomarkers and pathways, and uncover the biological mechanism...
November 2023: Heliyon
https://read.qxmd.com/read/37895912/recent-perspectives-on-cardiovascular-toxicity-associated-with-colorectal-cancer-drug-therapy
#17
REVIEW
Monu Kumar Kashyap, Shubhada V Mangrulkar, Sapana Kushwaha, Akash Ved, Mayur B Kale, Nitu L Wankhede, Brijesh G Taksande, Aman B Upaganlawar, Milind J Umekar, Sushruta Koppula, Spandana Rajendra Kopalli
Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment...
October 11, 2023: Pharmaceuticals
https://read.qxmd.com/read/37855416/activation-of-mitogen-activated-protein-kinase-signaling-and-development-of-papillary-thyroid-carcinoma-in-thyroid-stimulating-hormone-receptor-d633h-knockin-mice
#18
JOURNAL ARTICLE
Markus Eszlinger, Alexandra Stephenson, Shideh Mirhadi, Konrad Patyra, Michael F Moran, Moosa Khalil, Jukka Kero, Ralf Paschke
OBJECTIVE: Nonautoimmune hyperthyroidism (NAH) is rare and occurs due to a constitutively activating thyroid stimulating hormone receptor (TSHR) mutation. In contrast to other thyroid nodules, no further evaluation for malignancy is recommended for hot thyroid nodules. In the first model for NAH in mice nearly all homozygous mice had developed papillary thyroid cancer by 12 months of age. METHODS: To further evaluate these mice, whole exome sequencing and phosphoproteome analysis were employed in a further generation of mice to identify any other mutations potentially responsible and to identify the pathways involved in thyroid carcinoma development...
December 1, 2023: European Thyroid Journal
https://read.qxmd.com/read/37808191/preclinical-characterization-of-tunlametinib-a-novel-potent-and-selective-mek-inhibitor
#19
JOURNAL ARTICLE
Yahong Liu, Ying Cheng, Gongchao Huang, Xiangying Xia, Xingkai Wang, Hongqi Tian
Background: Aberrant activation of RAS-RAF-MEK-ERK signaling pathway has been implicated in more than one-third of all malignancies. MEK inhibitors are promising therapeutic approaches to target this signaling pathway. Though four MEK inhibitors have been approved by FDA, these compounds possess either limited efficacy or unfavorable PK profiles with toxicity issues, hindering their broadly application in clinic. Our efforts were focused on the design and development of a novel MEK inhibitor, which subsequently led to the discovery of tunlametinib...
2023: Frontiers in Pharmacology
https://read.qxmd.com/read/37775019/kz02-enhances-the-radiosensitivity-of-braf-mutated-crc-in-vitro-and-in-vivo
#20
JOURNAL ARTICLE
Yuying Guo, Xuejiao Li, Renbin Yuan, Jingming Ren, Yichi Huang, Yanxiang Yu, Hongqi Tian
Colorectal cancer (CRC) is a common malignant tumor with a high incidence and mortality worldwide. Preoperative chemoradiotherapy is a common treatment for patients with metastatic colorectal cancer (mCRC) as it reduces colostomy and local recurrence. The RAS (rat sarcoma)-RAF (extracellular signal-regulated kinase)-MEK (mitogen-activated protein kinase)-ERK (extracellular signal-regulated kinase) pathway regulates important cellular processes in the CRC. Abnormal ERK activation stimulates cell growth and provides a survival advantage...
September 27, 2023: European Journal of Pharmacology
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