[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-373128-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-373128-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","its-all-downstream-from-here-rtkrafmekerk-pathway-resistance-mechanisms-in-glioblastoma","It’s all downstream from here - RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma","","Receptor tyrosine kinase (RTK)/Ras/Raf/MEK/ERK signaling is a highly tumorigenic pathway in cancer and is strongly hyperactivated in glioblastoma (GBM), yet therapeutic success is limited by acquired resistance. This review examines how inhibiting the RTK/Ras/Raf/MEK/ERK pathway alters transcription factors and how transcription factor dysregulation drives resistance to targeted therapy, radiation, and chemotherapy. Evidence from key studies is synthesized, concluding that transcription factors are promising co-targets.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/its-all-downstream-from-here-rtkrafmekerk-pathway-resistance-mechanisms-in-glioblastoma/373128/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/its-all-downstream-from-here-rtkrafmekerk-pathway-resistance-mechanisms-in-glioblastoma/373128.png","ImageObject",300,407,{"name":42,"@type":43},"Rowan","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-27","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is RTK/Ras/Raf/MEK/ERK signaling important in glioblastoma?","Question",{"text":63,"@type":64},"The pathway is frequently hyperactivated in GBM and links cell-surface signals to transcription factors that regulate major tumor-related processes. It is therefore closely tied to GBM aggressiveness and survival.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What is the main focus of the review?",{"text":68,"@type":64},"The review investigates how inhibiting the RTK/Ras/Raf/MEK/ERK pathway changes transcription factors and how this dysregulation contributes to acquired resistance mechanisms in GBM.",{"name":70,"@type":61,"acceptedAnswer":71},"How does transcription factor dysregulation relate to treatment resistance?",{"text":72,"@type":64},"After RTK/Ras/Raf/MEK/ERK pathway inhibition, transcription factors undergo significant dysregulation. 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Although extensive research has focused on developing therapeutics targeting this pathway, clinical success remains elusive due to the emergence of resistance mechanisms.  \nObjective This review investigates how inhibition of the RTK/Ras/Raf/MEK/ERK pathway alters transcription factors, contributing to acquired resistance mechanisms in GBM. It also highlights the critical role of transcription factor dysregulation in therapeutic resistance.  \nMethods & Results Findings from key studies on the RTK/Ras/Raf/MEK/ERK pathway in GBM were synthesized to explore the role of transcription factor dysregulation in resistance to targeted therapies, radiation, and chemotherapy. The review highlights that transcription factors undergo significant dysregulation following RTK/Ras/Raf/MEK/ERK pathway inhibition, contributing to therapeutic resistance.  \nConclusion Transcription factors are promising targets for overcoming treatment resistance in GBM, with cotreatment strategies combining RTK/Ras/Raf/MEK/ERK pathway inhibitors and transcription factor-targeted therapies presenting a novel approach. Despite the challenges of targeting complex structures and interactions, advancements in drug development and precision technologies hold great potential. Continued research is essential to refine these strategies and improve outcomes for GBM and other aggressive cancers.  \nKeywords Glioblastoma · RTK/Raf/MEK/ERK inhibitors · Resistance mechanisms · Transcription factors  \nIntroduction  \nIDH wild-type glioblastoma (GBM) is the most common and lethal primary brain tumour, primarily due to challenges in achieving gross total resection and the presence of highly invasive cells that contribute to resistance to  \n* Gelareh Zadeh [gelareh.zadeh@uhn.ca](gelareh.zadeh@uhn.ca)  \n* Severa Bunda [severa.bunda@uhn.ca](severa.bunda@uhn.ca)  \n1 MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada  \n2 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada  \n3 Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada  \nstandard of care radiation and chemotherapy [1] . Despite a highly heterogeneous oncogenetic profile, aberrant kinase signalling is nearly a universal feature of GBM [2 , 3] . In part, the aggressive nature of GBM and other lethal tumors has been attributed to the hyperactivation of receptor tyrosine kinase (RTK) and its downstream signalling pathways, including the Ras/Raf/MEK/Extracellular signal regulated kinase (ERK) activation [2–4] . This signalling cascade directly couples signals from cell surface receptors to transcription factors that modulate gene expression. Following RTK activation, ERK enters the nucleus to regulate the activity of various transcription factors (both repressors and activators) which in turn modulate a variety of cellular functions including those implicated in tumorigenesis such as apoptosis, cell cycle progression, cell migration, differentiation, metabolism, and proliferation [5](Fig. 1) . Aberrant activation of the RTK/Raf/Ras/ MEK/ERK signaling pathway, often driven by mutations  \nFig. 1 Schematic depicting the RTK/Ras/Raf/MEK/ERK pathway and key processes they regulate. Red stars denote frequent","cbCaiukdmegROcV5","https://ap.wps.com/l/cbCaiukdmegROcV5","pdf",1290448,"English","# Abstract\n## Background\n## Objective\n## Methods & Results\n## Conclusion\n# Introduction\n## Overview of RTK/Ras/Raf/MEK/ERK signaling in GBM\n## Resistance mechanisms and transcription factor dysregulation\n# Transcription factors in GBM resistance","[{\"question\":\"Why is RTK/Ras/Raf/MEK/ERK signaling important in glioblastoma?\",\"answer\":\"The pathway is frequently hyperactivated in GBM and links cell-surface signals to transcription factors that regulate major tumor-related processes. It is therefore closely tied to GBM aggressiveness and survival.\"},{\"question\":\"What is the main focus of the review?\",\"answer\":\"The review investigates how inhibiting the RTK/Ras/Raf/MEK/ERK pathway changes transcription factors and how this dysregulation contributes to acquired resistance mechanisms in GBM.\"},{\"question\":\"How does transcription factor dysregulation relate to treatment resistance?\",\"answer\":\"After RTK/Ras/Raf/MEK/ERK pathway inhibition, transcription factors undergo significant dysregulation. This supports resistance to targeted therapies and also contributes to resistance to radiation and chemotherapy.\"}]","It’s all downstream from here - RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma | PDF",1790197010,48]