HSPA5 and FGFR1 Genes in the Mesenchymal Subtype of Glioblastoma Can Improve a Treatment Efficacy

Overview

Journal Anim Cells Syst (Seoul)

Specialty Biology

Date 2024 May 21

PMID 38770056

Authors

Ju Young Lee

Jongkeun Park

Dongwan Hong

Affiliations

Soon will be listed here.

Abstract

Tyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 () and fibroblast growth factor receptor 1 (). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

References

Kim H, Kim T, Hoffman N, Xiao D, James D, Humphrey S . PhosR enables processing and functional analysis of phosphoproteomic data. Cell Rep. 2021; 34(8):108771. DOI: 10.1016/j.celrep.2021.108771. View

Yamini B . NF-κB, Mesenchymal Differentiation and Glioblastoma. Cells. 2018; 7(9). PMC: 6162779. DOI: 10.3390/cells7090125. View

Ritchie M, Phipson B, Wu D, Hu Y, Law C, Shi W . limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43(7):e47. PMC: 4402510. DOI: 10.1093/nar/gkv007. View

Liu H, Zhang W, Zou B, Wang J, Deng Y, Deng L . DrugCombDB: a comprehensive database of drug combinations toward the discovery of combinatorial therapy. Nucleic Acids Res. 2019; 48(D1):D871-D881. PMC: 7145671. DOI: 10.1093/nar/gkz1007. View

Das S, Marsden P . Angiogenesis in glioblastoma. N Engl J Med. 2013; 369(16):1561-3. PMC: 5378489. DOI: 10.1056/NEJMcibr1309402. View

Knijnenburg T, Wang L, Zimmermann M, Chambwe N, Gao G, Cherniack A . Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep. 2018; 23(1):239-254.e6. PMC: 5961503. DOI: 10.1016/j.celrep.2018.03.076. View

Tan M, Sandanaraj E, Chong Y, Lim S, Koh L, Ng W . A STAT3-based gene signature stratifies glioma patients for targeted therapy. Nat Commun. 2019; 10(1):3601. PMC: 6689009. DOI: 10.1038/s41467-019-11614-x. View

Berte N, Piee-Staffa A, Piecha N, Wang M, Borgmann K, Kaina B . Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs. Mol Cancer Ther. 2016; 15(11):2665-2678. DOI: 10.1158/1535-7163.MCT-16-0176. View

Li B, Gu X, Zhang H, Xiong H . Comprehensive analysis of the prognostic value and immune implications of the TTK gene in lung adenocarcinoma: a meta-analysis and bioinformatics analysis. Anim Cells Syst (Seoul). 2022; 26(3):108-118. PMC: 9246214. DOI: 10.1080/19768354.2022.2079718. View

10.

Morrison R, Yamaguchi F, Bruner J, Tang M, McKEEHAN W, Berger M . Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. Cancer Res. 1994; 54(10):2794-9. View

11.

Olmez I, Love S, Xiao A, Manigat L, Randolph P, McKenna B . Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha. Neuro Oncol. 2017; 20(2):192-202. PMC: 5777487. DOI: 10.1093/neuonc/nox119. View

12.

Verhaak R, Hoadley K, Purdom E, Wang V, Qi Y, Wilkerson M . Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010; 17(1):98-110. PMC: 2818769. DOI: 10.1016/j.ccr.2009.12.020. View

13.

Behnan J, Finocchiaro G, Hanna G . The landscape of the mesenchymal signature in brain tumours. Brain. 2019; 142(4):847-866. PMC: 6485274. DOI: 10.1093/brain/awz044. View

14.

Lin X, Zheng L, Song H, Xiao J, Pan B, Chen H . Effects of microRNA-183 on epithelial-mesenchymal transition, proliferation, migration, invasion and apoptosis in human pancreatic cancer SW1900 cells by targeting MTA1. Exp Mol Pathol. 2017; 102(3):522-532. DOI: 10.1016/j.yexmp.2017.05.009. View

15.

Sidaway P . CNS cancer: Glioblastoma subtypes revisited. Nat Rev Clin Oncol. 2017; 14(10):587. DOI: 10.1038/nrclinonc.2017.122. View

16.

Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L . Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017; 32(1):42-56.e6. PMC: 5599156. DOI: 10.1016/j.ccell.2017.06.003. View

17.

Pearson J, Regad T . Targeting cellular pathways in glioblastoma multiforme. Signal Transduct Target Ther. 2017; 2:17040. PMC: 5661637. DOI: 10.1038/sigtrans.2017.40. View

18.

Shao Y, Ren W, Dai H, Yang F, Li X, Zhang S . SKP2 Contributes to AKT Activation by Ubiquitination Degradation of PHLPP1, Impedes Autophagy, and Facilitates the Survival of Thyroid Carcinoma. Mol Cells. 2023; 46(6):360-373. PMC: 10258456. DOI: 10.14348/molcells.2022.2242. View

19.

Yu M, Chen J, Xu Z, Yang B, He Q, Luo P . Development and safety of PI3K inhibitors in cancer. Arch Toxicol. 2023; 97(3):635-650. PMC: 9968701. DOI: 10.1007/s00204-023-03440-4. View

20.

Pan P, Magge R . Mechanisms of EGFR Resistance in Glioblastoma. Int J Mol Sci. 2020; 21(22). PMC: 7696540. DOI: 10.3390/ijms21228471. View