Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma

Gao Guo, Ke Gong, Vineshkumar Thidil Puliyappadamba, Nishah Panchani, Edward Pan, Bipasha Mukherjee, Ziba Damanwalla, Sabrina Bharia, Kimmo J. Hatanpaa, David E. Gerber, Bruce E. Mickey, Toral R. Patel, Jann N. Sarkaria, Dawen Zhao, Sandeep Burma, Amyn A. Habib

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. METHODS: We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. RESULTS: The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. CONCLUSION: EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.

Original languageEnglish (US)
Pages (from-to)1529-1539
Number of pages11
JournalNeuro-oncology
Volume21
Issue number12
DOIs
StatePublished - Dec 17 2019

Keywords

  • adaptive response
  • EGFR
  • glioblastoma
  • temozolomide
  • TNF

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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  • Cite this

    Guo, G., Gong, K., Puliyappadamba, V. T., Panchani, N., Pan, E., Mukherjee, B., Damanwalla, Z., Bharia, S., Hatanpaa, K. J., Gerber, D. E., Mickey, B. E., Patel, T. R., Sarkaria, J. N., Zhao, D., Burma, S., & Habib, A. A. (2019). Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma. Neuro-oncology, 21(12), 1529-1539. https://doi.org/10.1093/neuonc/noz127