TY - JOUR
T1 - Non-metabolic functions of phosphofructokinase-1 orchestrate tumor cellular invasion and genome maintenance under bevacizumab therapy
AU - Lim, Yi Chieh
AU - E Jensen, Kamilla
AU - Aguilar-Morante, Diana
AU - Vardouli, Lina
AU - Vitting-Seerup, Kristoffer
AU - C Gimple, Ryan
AU - Wu, Qiulian
AU - Pedersen, Henriette
AU - Elbaek, Kirstine J
AU - Gromova, Irina
AU - Ihnatko, Robert
AU - Kristensen, Bjarne W
AU - Petersen, Jeanette K
AU - Skjoth-Rasmussen, Jane
AU - Flavahan, William
AU - Rich, Jeremy N
AU - Hamerlik, Petra
N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
PY - 2023/2/14
Y1 - 2023/2/14
N2 - BACKGROUND: Glioblastoma (GBM) is a highly lethal malignancy for which neoangiogenesis serves as a defining hallmark. The anti-VEGF antibody, bevacizumab, has been approved for the treatment of recurrent GBM, but resistance is universal.METHODS: We analyzed expression data of GBM patients treated with bevacizumab to discover potential resistance mechanisms. Patient-derived xenografts (PDXs) and cultures were interrogated for effects of phosphofructokinase-1, muscle isoform (PFKM) loss on tumor cell motility, migration, and invasion through genetic and pharmacologic targeting.RESULTS: We identified PFKM as a driver of bevacizumab resistance. PFKM functions dichotomize based on subcellular location: cytosolic PFKM interacted with KIF11, a tubular motor protein, to promote tumor invasion, whereas nuclear PFKM safeguarded genomic stability of tumor cells through interaction with NBS1. Leveraging differential transcriptional profiling, bupivacaine phenocopied genetic targeting of PFKM, and enhanced efficacy of bevacizumab in preclinical GBM models in vivo.CONCLUSION: PFKM drives novel molecular pathways in GBM, offering a translational path to a novel therapeutic paradigm.
AB - BACKGROUND: Glioblastoma (GBM) is a highly lethal malignancy for which neoangiogenesis serves as a defining hallmark. The anti-VEGF antibody, bevacizumab, has been approved for the treatment of recurrent GBM, but resistance is universal.METHODS: We analyzed expression data of GBM patients treated with bevacizumab to discover potential resistance mechanisms. Patient-derived xenografts (PDXs) and cultures were interrogated for effects of phosphofructokinase-1, muscle isoform (PFKM) loss on tumor cell motility, migration, and invasion through genetic and pharmacologic targeting.RESULTS: We identified PFKM as a driver of bevacizumab resistance. PFKM functions dichotomize based on subcellular location: cytosolic PFKM interacted with KIF11, a tubular motor protein, to promote tumor invasion, whereas nuclear PFKM safeguarded genomic stability of tumor cells through interaction with NBS1. Leveraging differential transcriptional profiling, bupivacaine phenocopied genetic targeting of PFKM, and enhanced efficacy of bevacizumab in preclinical GBM models in vivo.CONCLUSION: PFKM drives novel molecular pathways in GBM, offering a translational path to a novel therapeutic paradigm.
KW - Bevacizumab/pharmacology
KW - Brain Neoplasms/drug therapy
KW - Glioblastoma/drug therapy
KW - Humans
KW - Phosphofructokinase-1
UR - http://www.scopus.com/inward/record.url?scp=85148113537&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noac135
DO - 10.1093/neuonc/noac135
M3 - Journal article
C2 - 35608632
SN - 1522-8517
VL - 25
SP - 248
EP - 260
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 2
ER -