It’s all downstream from here - RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma

Sep 23, 2026

Uploaded by Rowan

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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Abstract

Background

Objective

Methods & Results

Conclusion

Introduction

Overview of RTK/Ras/Raf/MEK/ERK signaling in GBM

Resistance mechanisms and transcription factor dysregulation

Transcription factors in GBM resistance

Journal of Neuro-Oncology (2025) 172:327–345 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1060-024-04930-w It’s all downstream from here: RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma Rebeca Yakubov1,2 · Ramneet Kaloti1,2 · Phooja Persaud1,2 · Anna McCracken1,2 · Gelareh Zadeh1,2,3 · Severa Bunda1,2 Received: 6 November 2024 / Accepted: 24 December 2024 / Published online: 16 January 2025 © The Author(s) 2025 Abstract Background The receptor tyrosine kinase (RTK)/Ras/Raf/MEK/ERK signaling pathway is one of the most tumorigenic pathways in cancer, with its hyperactivation strongly linked to the aggressive nature of glioblastoma (GBM) . Although extensive research has focused on developing therapeutics targeting this pathway, clinical success remains elusive due to the emergence of resistance mechanisms. Objective 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. Methods & 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. Conclusion 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. Keywords Glioblastoma · RTK/Raf/MEK/ERK inhibitors · Resistance mechanisms · Transcription factors Introduction IDH 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 * Gelareh Zadeh [gelareh.zadeh@uhn.ca](gelareh.zadeh@uhn.ca) * Severa Bunda [severa.bunda@uhn.ca](severa.bunda@uhn.ca) 1 MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada 2 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3 Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada standard 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 Fig. 1 Schematic depicting the RTK/Ras/Raf/MEK/ERK pathway and key processes they regulate. Red stars denote frequent

FAQs

Why is RTK/Ras/Raf/MEK/ERK signaling important in glioblastoma?

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.

What is the main focus of the review?

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.

How does transcription factor dysregulation relate to treatment resistance?

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.

Sep 23, 2026

Uploaded by Rowan