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Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma

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Abstract

Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma’s lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis.

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Abbreviations

ALK:

Anaplastic Lymphoma Kinase

AKT:

Protein Kinase B

ARF:

ADP Ribosylation Factor

BAD:

Bcl-2 Associated Death promoter

Bcl-2:

B-Cell Lymphoma 2

BIM:

Bcl-2-like protein 11 gene

c-myc:

Transcriptional Promoter Gene

Cdc25A:

Cell Division Cycle 25 Homolog A

CNS:

Central Nervous System

EGFR:

Epidermal Growth Factor Receptor

Elk-1:

E twenty-six-like transcription factor 1

ERK:

Extracellular signal-Related Kinase

FASL:

(CD95L) Fas Ligand gene

FOXO:

Forkhead Box protein O1 (aka forkhead in rhabdomyosarcoma)

GFAP:

Glial Fibrillary Acidic Protein

Gsk3β:

Glycogen synthase kinase-3 (β isoform)

HGF:

Hepatocyte Growth Factor

HGFR:

(aka MET) Hepatocyte Growth Factor Receptor

HIF-1α:

Hypoxia Inducible Factor

IGF-1:

Insulin-like Growth Factor

INK4a:

(aka CDKN2A) Cyclin-dependent kinase inhibitor 2a

MDM2:

Murine Double Minute oncogene product

MEK:

Mitogen-activated protein kinase kinase

mTOR:

Mammalian Target of Rapamycin

NBM:

Neuroblastoma

NFκB:

Nuclear Factor kappa B

PDGF:

Platelet Derived Growth Factor

PI3K:

Phosphoinositide 3-kinase

PIP2:

Phosphatidylinositol (4,5)-bisphosphate

PIP3:

Phosphatidylinositol (3,4,5)-triphosphate

PLT:

Pleiotrophin

PNS:

Peripheral Nervous System

PTEN:

Phosphatase and Tensin Homologue

RAF:

Rapidly Accelerated Fibrosarcoma (viral gene)

Ras:

GTPase dependent intracellular signal protein family

RB1:

Retinoblastoma Protein 1

RTK:

Receptor Tyrosine Kinase

TMZ:

Temozolomide

TP53:

Tumor Protein 53

TSC2:

Tuberous Sclerosis Protein 2

STAT3/5:

Signal Transducer and Activator of Transcription

VEGF(R):

Vascular Endothelial Growth Factor (Receptor)

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Acknowledgments

Completion of this project was made possible by funding from the National Institutes of Health (NIH) and National Institute of Neurological Disorders and Stroke (NINDS): (NS31622, NS-38146, NS-57811, and NS-41088), the State of South Carolina Spinal Cord Injury Research Project (SCSCIRF), VA (1I01BX001262-01A2), Pfizer, Inc., and the Jerry Zucker Fund for Brain Tumor Research of the MUSC Foundation.

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Authors and Affiliations

  1. Department of Neurosciences and MUSC Brain & Spine Tumor Program, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA

    Gerald C. Wallace IV, Yaenette N. Dixon-Mah, W. Alex Vandergrift III, Catherine P. Haar, Amber M. Mittendorf, Sunil J. Patel, Naren L. Banik, Pierre Giglio & Arabinda Das

  2. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA

    Swapan K. Ray

  3. Ralph H. Johnson VA Medical Center, Charleston, SC, 29425, USA

    Naren L. Banik

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Correspondence to Arabinda Das.

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Wallace, G.C., Dixon-Mah, Y.N., Vandergrift, W.A. et al. Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma. Metab Brain Dis 28, 355–366 (2013). https://doi.org/10.1007/s11011-013-9401-7

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  • DOI: https://doi.org/10.1007/s11011-013-9401-7

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