Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines.

Abstract

BACKGROUND AND PURPOSE:

Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines").

MATERIALS AND METHODS:

Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling.

RESULTS:

Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance.

CONCLUSION:

GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.

• Authors: Joshua C Anderson, Christine W Duarte, Karim Welaya, Timothy D Rohrbach, Markus Bredel, Eddy S Yang, Nirmal V Choradia, Jaideep V Thottassery, George Yancey Gillespie, James A Bonner, Christopher D Willey
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 111 Issue 3 Pg. 468-74 (Jun 2014) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 24813092 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Alkylating
• Dacarbazine
• Protein-Tyrosine Kinases
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Brain Neoplasms (drug therapy, enzymology, pathology, radiotherapy)
• Cell Line, Tumor
• Dacarbazine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm
• Glioblastoma (drug therapy, enzymology, pathology, radiotherapy)
• Humans
• Mice
• Mice, Nude
• Protein-Tyrosine Kinases (metabolism)
• Radiation Tolerance
• Temozolomide
• Xenograft Model Antitumor Assays