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Ruthenium Drug BOLD-100 Regulates BRAFMT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation

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Title: Ruthenium Drug BOLD-100 Regulates BRAFMT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation
Authors: Daryl Griffin, Robbie Carson, Debbie Moss, Tamas Sessler, Deborah Lavin, Vijay K. Tiwari, Shivaali Karelia, Richard Kennedy, Kienan I. Savage, Simon McDade, Adam Carie, Jim Pankovich, Mark Bazett, Sandra Van Schaeybroeck
Source: Mol Cancer Res
Griffin, D, Carson, R, Moss, D, Sessler, T, Lavin, D, Tiwari, V, Karelia, S, Kennedy, R, Savage, K I, McDade, S, Carie, A, Pankovich, J, Bazett, M & Van Schaeybroeck, S 2024, 'Ruthenium drug BOLD-100 regulates BRAFMT colorectal cancer cell apoptosis through AhR/ROS/ATR signaling axis modulation', Molecular Cancer Research, vol. 22, no. 12, pp. 1088-1101. https://doi.org/10.1158/1541-7786.MCR-24-0151
Publisher Information: American Association for Cancer Research (AACR), 2024.
Publication Year: 2024
Subject Terms: Proto-Oncogene Proteins B-raf, Ataxia Telangiectasia Mutated Proteins/metabolism, name=Oncology, name=Cancer Research, colorectal cancer, Apoptosis, Ataxia Telangiectasia Mutated Proteins, Cancer Genes and Networks, Cell Line, ruthenium drug, Reactive Oxygen Species/metabolism, Signal Transduction/drug effects, Cell Line, Tumor, Proto-Oncogene Proteins B-raf/genetics, Receptors, Basic Helix-Loop-Helix Transcription Factors, Humans, name=SDG 3 - Good Health and Well-being, Tumor, cell apoptosis, Apoptosis/drug effects, Colorectal Neoplasms/drug therapy, 3. Good health, Receptors, Aryl Hydrocarbon, Aryl Hydrocarbon/metabolism, BOLD-100, BRAFMT, Colorectal Neoplasms, Reactive Oxygen Species, Signal Transduction
Description: Patients with class I V600EBRAF-mutant (MT) colorectal cancer exhibit a poor prognosis, and their response to combined anti-BRAF/EGFR inhibition remains limited. An unmet need exits for further understanding the biology of V600EBRAFMT colorectal cancer. We used differential gene expression of BRAFWT and MT colorectal cancer cells to identify pathways underpinning BRAFMT colorectal cancer. We tested a panel of molecularly/genetically subtyped colorectal cancer cells for their sensitivity to the unfolded protein response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified significant enrichment of the UPR and DNA repair pathways in BRAFMT colorectal cancer. We found that oncogenic BRAF plays a crucial role in mediating the response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ataxia telangiectasia and Rad3-related (ATR) as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species levels following treatment with BOLD-100, which promoted ATR/CHK1 activation and apoptosis. Furthermore, activation of reactive oxygen species/ATR/CHK1 following BOLD-100 was mediated through the AhR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results highlight a possible novel therapeutic opportunity for BRAFMT colorectal cancer. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (e.g., by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT colorectal cancer.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1557-3125
1541-7786
DOI: 10.1158/1541-7786.mcr-24-0151
Access URL: https://pubmed.ncbi.nlm.nih.gov/39083088
https://pure.qub.ac.uk/en/publications/357b4c8d-d077-4033-8c9a-433d6c961788
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
Accession Number: edsair.doi.dedup.....fe350e22e7b1e14690404282bbde684c
Database: OpenAIRE
Description
Abstract:Patients with class I V600EBRAF-mutant (MT) colorectal cancer exhibit a poor prognosis, and their response to combined anti-BRAF/EGFR inhibition remains limited. An unmet need exits for further understanding the biology of V600EBRAFMT colorectal cancer. We used differential gene expression of BRAFWT and MT colorectal cancer cells to identify pathways underpinning BRAFMT colorectal cancer. We tested a panel of molecularly/genetically subtyped colorectal cancer cells for their sensitivity to the unfolded protein response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified significant enrichment of the UPR and DNA repair pathways in BRAFMT colorectal cancer. We found that oncogenic BRAF plays a crucial role in mediating the response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ataxia telangiectasia and Rad3-related (ATR) as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species levels following treatment with BOLD-100, which promoted ATR/CHK1 activation and apoptosis. Furthermore, activation of reactive oxygen species/ATR/CHK1 following BOLD-100 was mediated through the AhR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results highlight a possible novel therapeutic opportunity for BRAFMT colorectal cancer. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (e.g., by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT colorectal cancer.
ISSN:15573125
15417786
DOI:10.1158/1541-7786.mcr-24-0151