Kinomic Alterations in Atypical Meningioma
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http://orcid.org/0000-0001-9953-0279
Abstract
Background: We sought to profile Atypical Meningioma in a high-throughput manner to better understand the altered signaling within these tumors and specifically the kinases altered in recurrent atypical meningioma. Kinomic Profiles could be used to identify prognostic biomarkers for responders/non-responders to classify future patients that are unlikely to benefit from current therapies. Directly these results could be used to identify drug-actionable kinase targets as well.
Methods: Peptide-substrate microarray kinase activity analysis was conducted with a PamStation®12 analyzing the tyrosine kinome in each tumor kinetically against ~144 target peptides. These data were then analyzed relative to clinical outcome (e.g., tumor recurrence).
Results: 3 major clusters of atypical meningiomas were identified with highly variant peptides primarily being targets of EGFR family, ABL, BRK and BMX kinases. Kinomic analysis of recurrent atypical meningiomas indicated patterns of increased phosphorylation of BMX, TYRO3 and FAK substrates as compared to non-recurrent tumors.
Conclusion: The atypical meningiomas profiled here exhibited molecular sub-clustering that may have phenotypic corollaries predictive of outcome. Recurrent tumors had increases in kinase activity that may predict resistance to current therapies, and may guide selection of directed therapies. Taken together these data further the understanding of kinomic alteration in atypical meningioma, and the processes that may not only mediate recurrence, but additionally may identify kinase targets for intervention.
Article Details
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References
Anderson, J. C., Duarte, C. W., Welaya, K., Rohrbach, T. D., Bredel, M., Yang, E. S., . . . Willey, C. D. (2014). Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines. Radiother Oncol, 111(3), 468-474. doi: 10.1016/j.radonc.2014.04.010
Anderson, J. C., Minnich, D. J., Dobelbower, M. C., Denton, A. J., Dussaq, A. M., Gilbert, A. N., . . . Willey, C. D. (2014). Kinomic profiling of electromagnetic navigational bronchoscopy specimens: a new approach for personalized medicine. PLoS One, 9(12), e116388. doi: 10.1371/journal.pone.0116388
Blanc, J., Geney, R., & Menet, C. (2013). Type II kinase inhibitors: an opportunity in cancer for rational design. Anticancer Agents Med Chem, 13(5), 731-747.
Bostrom, J., Meyer-Puttlitz, B., Wolter, M., Blaschke, B., Weber, R. G., Lichter, P., . . . Reifenberger, G. (2001). Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas Am J Pathol (Vol. 159, pp. 661-669). United States.
Bujko, M., Kober, P., Tysarowski, A., Matyja, E., Mandat, T., Bonicki, W., & Siedlecki, J. A. (2014). EGFR, PIK3CA, KRAS and BRAF mutations in meningiomas. Oncol Lett, 7(6), 2019-2022. doi: 10.3892/ol.2014.2042
Choy, W., Kim, W., Nagasawa, D., Stramotas, S., Yew, A., Gopen, Q., . . . Yang, I. (2011). The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments. Neurosurg Focus, 30(5), E6. doi: 10.3171/2011.2.focus1116
Duverger, A., Wolschendorf, F., Anderson, J. C., Wagner, F., Bosque, A., Shishido, T., . . . Kutsch, O. (2013). Kinase control of Latent HIV-1 Infection: PIM-1 Kinase as a Major Contributor to HIV-1 Reactivation. J Virol. doi: 10.1128/JVI.02682-13
Fang, Z., Grutter, C., & Rauh, D. (2013). Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol, 8(1), 58-70. doi: 10.1021/cb300663j
Golubovskaya, V. M. (2014). Targeting FAK in human cancer: from finding to first clinical trials. Front Biosci (Landmark Ed), 19, 687-706.
Graham, D. K., DeRyckere, D., Davies, K. D., & Earp, H. S. (2014). The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer, 14(12), 769-785.
James, M. F., Han, S., Polizzano, C., Plotkin, S. R., Manning, B. D., Stemmer-Rachamimov, A. O., . . . Ramesh, V. (2009). NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth Mol Cell Biol (Vol. 29, pp. 4250-4261). United States.
Jarboe, J. S., Dutta, S., Velu, S. E., & Willey, C. D. (2013). Mini-review: bmx kinase inhibitors for cancer therapy. Recent Pat Anticancer Drug Discov, 8(3), 228-238.
Jenkinson, M. D., Weber, D. C., Haylock, B. J., Mallucci, C. L., Zakaria, R., & Javadpour, M. (2015). Atypical meningioma: current management dilemmas and prospective clinical trials. J Neurooncol, 121(1), 1-7. doi: 10.1007/s11060-014-1620-1
Kaley, T. J., Wen, P., Schiff, D., Ligon, K., Haidar, S., Karimi, S., . . . Omuro, A. (2015). Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol, 17(1), 116-121. doi: 10.1093/neuonc/nou148
Komotar, R. J., Iorgulescu, J. B., Raper, D. M., Holland, E. C., Beal, K., Bilsky, M. H., . . . Gutin, P. H. (2012). The role of radiotherapy following gross-total resection of atypical meningiomas. J Neurosurg, 117(4), 679-686. doi: 10.3171/2012.7.JNS112113
Mawrin, C., Sasse, T., Kirches, E., Kropf, S., Schneider, T., Grimm, C., . . . Dietzmann, K. (2005). Different activation of mitogen-activated protein kinase and Akt signaling is associated with aggressive phenotype of human meningiomas Clin Cancer Res (Vol. 11, pp. 4074-4082). United States.
Norden, A. D., Drappatz, J., & Wen, P. Y. (2007). Targeted drug therapy for meningiomas. Neurosurg Focus, 23(4), E12. doi: 10.3171/FOC-07/10/E12
Powers, A. D., & Palecek, S. P. (2012). Protein analytical assays for diagnosing, monitoring, and choosing treatment for cancer patients. J Healthc Eng, 3(4), 503-534. doi: 10.1260/2040-2295.3.4.503
Sikkema, A. H., Diks, S. H., den Dunnen, W. F., ter Elst, A., Scherpen, F. J., Hoving, E. W., . . . de Bont, E. S. (2009). Kinome profiling in pediatric brain tumors as a new approach for target discovery Cancer Res (Vol. 69, pp. 5987-5995). United States.
Simpson, D. (1957). The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry, 20(1), 22-39.
Wang, Q., Zorn, J. A., & Kuriyan, J. (2014). A structural atlas of kinases inhibited by clinically approved drugs. Methods Enzymol, 548, 23-67. doi: 10.1016/B978-0-12-397918-6.00002-1