Rho-associated kinase is a therapeutic target in neuroblastoma

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Significance

Despite intensive therapy, the cure rate for children diagnosed with high-risk neuroblastoma is still below 50%, accentuating the need for more effective therapies. Recurrent somatic mutations are relatively infrequent in neuroblastoma. We show that approximately 30% of neuroblastoma contains mutations in genes regulating Rho/Rac signaling. The mutations may be associated with activation of downstream Rho-associated kinases (ROCKs). High ROCK2 expression is associated with poor patient survival. Inhibition of ROCK activity suppresses the growth of neuroblastoma in preclinical in vivo models. ROCK inhibitors induce differentiation of neuroblastoma cells partly by glycogen synthase kinase 3β-mediated phosphorylation and degradation of MYCN proteins. These findings suggest that inhibitors of ROCK may represent a therapeutic opportunity for children with high-risk neuroblastoma.

Abstract

Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH- MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.

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Most cited references 23

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The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 8 August 2017

Publication date (Electronic): 24 July 2017

Publication date PMC-release: 24 July 2017

Volume: 114

Issue: 32

Pages: E6603-E6612

Affiliations

[1] ^aChildhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet , 171 76 Stockholm, Sweden;

[2] ^bDepartment of Pathology and Genetics, Sahlgrenska Academy, University of Gothenburg , 405 30 Gothenburg, Sweden;

[3] ^cDepartment of Medical Biology, University of Tromsö , 9037 Tromso, Norway;

[4] ^dPediatric Unit, Department of Women’s and Children’s Health, Karolinska Institutet , 171 76 Stockholm, Sweden;

[5] ^eDepartment of Oncology and Pathology, Karolinska Institutet , 171 76 Stockholm, Sweden

Author notes

²To whom correspondence may be addressed. Email: john.inge.johnsen@ 123456ki.se or malin.wickstrom@ 123456ki.se .

Edited by Dennis A. Carson, University of California, San Diego, La Jolla, CA, and approved June 29, 2017 (received for review April 19, 2017)

Author contributions: C.D., S.F., P.K., J.I.J., and M.W. designed research; C.D., S.F., T.A., B.S., J.L.-P., T.K.O., D.F., J.I.J., and M.W. performed research; B.S., E.H., T.M., B.B., and P.K. contributed new reagents/analytic tools; C.D., S.F., T.A., B.S., B.B., P.K., J.I.J., and M.W. analyzed data; and C.D., S.F., J.I.J., and M.W. wrote the paper.

¹J.I.J. and M.W. contributed equally to this work.