Identification of METex14 and PTPRZ1-MET Mutations as a Mechanism for Progressive, Recurrent, Chemo-Resistant High Grade Gliomas and a Novel Therapeutic Target
Introduction. Anaplastic astrocytomas (AAs) are grade 3 gliomas distinguished from low grade gliomas by higher malignancy, increased proliferation rate, and genetic mutation markers1-9. Patients, usually 30-50 years of age, undergo complete resection of this tumor, and then follow a stringent course of radiation and chemotherapy1-3,5,7. Problematically, these resected AAs reoccur as more aggressive, variably chemo-resistant, angiogenic secondary glioblastoma multiformes (sGBMs) with a much poorer prognosis1,4-9. Previous studies have identified the PTPRZ1-MET fusion gene as a common mutation between AAs and sGBMs and how it produces an “always-on” phosphorylated MET, inducing cell proliferation, migration, and angiogenesis1. This study identifies a co-occurring MET mutation in this specific cohort of patients and demonstrates even further how application of a novel MET inhibitor, PLB-1001, blocks these over proliferative effects5. Methods. To elucidate the sGBM mutational landscape, 188 sGBM genomic data were analyzed. After identification of a METex14 skipping mutation, the effect of increased MET signaling on STAT3, a downstream molecule in the MET pathway, was examined with immunohistochemistry and histology staining. Lentiviral vectors encoding ZM fusion and METex14 were transduced into a U87MG glioblastoma (GBM) mouse line. Subcutaneous xenografts treated with the MET-inhibitor PLB-1001 were then implanted intracranially5. Results. In analysis of the sGBM mutational landscape, both ZM fusion and METex14 skipping were identified to co-occur and found to be highly conserved in these high grade gliomas compared to primary GBM and low grade gliomas. The mutation, METex14 skipping, inhibited phosphorylation of the juxtamembrane component of the kinase, preventing its ubiquination and degradation. This subsequently prolonged MET’s stabilization and hyper-activated MET signaling and its downstream pathways such as STAT3, PI3K, and RAS. The novel potent MET-inhibitor, PLB-1001, demonstrated greater affinity for the ATP binding site on MET than crizotinib, a heavily studied MET inhibitor proven to reduce MET’s overactive effects, and inhibited the phosphorylation of STAT3, marking its inhibition of downstream MET signaling. In ZM-harboring U87 MG xenograft models, PLB-1001 was shown to reduce tumor volume by inhibition of MET signaling, proliferation, and uniquely angiogenesis5. Conclusions. Identification of ZM fusion and METex14 skipping as co-occurring mutations unique to AAs and sGBMs presents a highly specific MET signaling mechanism as a novel therapeutic target that can be specifically targeted by MET inhibitors such as PLB-1001. Although small, the subset of patients who present with these specific mutated tumors now have hope for possible future individualized therapies that show promise for better prognosis.
- Bao, Z.-S., Chen, H.-M., Yang, M.-Y., Zhang, C.-B., Yu, K., Ye, W.-L., Hu, B.-Q., Yan, W., Zhang, W., Akers, J., et al. (2014). RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. Genome Res. 24, 1765–1773.
- Dunbar E., Eppolito A, Henson JW, Genetic counseling and tumor predisposition in neuro-oncology practice, Neuro-Oncology Practice, Volume 3, Issue 1, March 2016, Pages 17–28, https://doi.org/10.1093/nop/npv051
- Grimm SA, Chamberlain MC. Anaplastic astrocytoma. CNS Oncol. 2016;5(3):145–157. doi:10.2217/cns-2016-0002
- Gherardi, E., Birchmeier, W., Birchmeier, C. et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12, 89–103 (2012). https://doi.org/10.1038/nrc3205
- Hu H, Mu Q, Bao Z, Chen Y, Liu Y, Chen J, Wang K, Wang Z, Nam Y, Jiang B, et al. Mutational landscape of secondary glioblastoma guides MET-targeted trial in brain tumor. Cell. 2018;175:1665–1678. doi: 10.1016/j.cell.2018.09.038
- Huang, M., Liu, T., Ma, P., Mitteer, R.A., Jr., Zhang, Z., Kim, H.J., Yeo, E., Zhang, D., Cai, P., Li, C., et al. (2016). c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J. Clin. Invest. 126, 1801–1814.
- Killela PJ, Pirozzi CJ, Reitman ZJ, et al. The genetic landscape of anaplastic astrocytoma. Oncotarget. 2014;5(6):1452–1457. doi:10.18632/oncotarget.1505
- Modrek AS, Golub D, Khan T, et al. Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2. Cell Rep. 2017;21(5):1267–1280. doi:10.1016/j.celrep.2017.10.009
- Zeng AL, et al. Tumour exosomes from cells harbouring PTPRZ1-MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma. Oncogene. 2017;36(38):5369–5381. doi: 10.1038/onc.2017.134.