Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha

Inan Olmez, Shawn Love, Aizhen Xiao, Laryssa Manigat, Peyton Randolph, Brian D. McKenna, Brian P. Neal, Salome Boroda, Ming Li, Breanna Brenneman, Roger Abounader, Desiree Floyd, Jeongwu Lee, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Erik P. Sulman, Marty Mayo, Daniel Gioeli, Michael WeberThurl E. Harris, Benjamin Purow

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Background The mesenchymal phenotype in glioblastoma (GBM) and other cancers drives aggressiveness and treatment resistance, leading to therapeutic failure and recurrence of disease. Currently, there is no successful treatment option available against the mesenchymal phenotype. Methods We classified patient-derived GBM stem cell lines into 3 subtypes: proneural, mesenchymal, and other/classical. Each subtype's response to the inhibition of diacylglycerol kinase alpha (DGKα) was compared both in vitro and in vivo. RhoA activation, liposome binding, immunoblot, and kinase assays were utilized to elucidate the novel link between DGKα and geranylgeranyltransferase I (GGTase I). Results Here we show that inhibition of DGKα with a small-molecule inhibitor, ritanserin, or RNA interference preferentially targets the mesenchymal subtype of GBM. We show that the mesenchymal phenotype creates the sensitivity to DGKα inhibition; shifting GBM cells from the proneural to the mesenchymal subtype increases ritanserin activity, with similar effects in epithelial-mesenchymal transition models of lung and pancreatic carcinoma. This enhanced sensitivity of mesenchymal cancer cells to ritanserin is through inhibition of GGTase I and downstream mediators previously associated with the mesenchymal cancer phenotype, including RhoA and nuclear factor-kappaB. DGKα inhibition is synergistic with both radiation and imatinib, a drug preferentially affecting proneural GBM. Conclusions Our findings demonstrate that a DGKα-GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM.

Original languageEnglish (US)
Pages (from-to)192-202
Number of pages11
JournalNeuro-Oncology
Volume20
Issue number2
DOIs
StatePublished - Jan 22 2018
Externally publishedYes

Keywords

  • GBM subtypes
  • diacylglycerol kinase alpha
  • geranylgeranyltransferase I
  • mesenchymal phenotype
  • ritanserin

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    Olmez, I., Love, S., Xiao, A., Manigat, L., Randolph, P., McKenna, B. D., Neal, B. P., Boroda, S., Li, M., Brenneman, B., Abounader, R., Floyd, D., Lee, J., Nakano, I., Godlewski, J., Bronisz, A., Sulman, E. P., Mayo, M., Gioeli, D., ... Purow, B. (2018). Targeting the mesenchymal subtype in glioblastoma and other cancers via inhibition of diacylglycerol kinase alpha. Neuro-Oncology, 20(2), 192-202. https://doi.org/10.1093/neuonc/nox119