Crizotinib and erlotinib inhibits growth of c-Met +/EGFRvIII + primary human glioblastoma xenografts

Clin Neurol Neurosurg. 2018 Aug;171:26-33. doi: 10.1016/j.clineuro.2018.02.041. Epub 2018 Mar 9.


Objectives: Receptor tyrosine kinases (RTK), such as c-Met and epidermal growth factor receptor (EGFR), are implicated in the malignant progression of glioblastoma. Studies show that RTK systems can co-modulate distinct and overlapping oncogenic downstream signaling pathways. EGFRvIII, a constitutively activated EGFR deletion mutant variant, leads to increased tumor growth and diminishes the tumor growth response to HGF: c-Met pathway inhibitor therapy. Conversely, activation of the c-Met pathway diminishes the tumor growth response to EGFR pathway inhibitors. Previously we reported that EGFRvIII and c-Met pathway inhibitors synergize to inhibit tumor growth in isogenic GBM cell lines engineered to express EGFRvIII. More recently, studies suggest that despite targeting RTK signaling in glioblastoma multiforme, a subpopulation of stem-like tumor-propagating cells can persist to replenish the tumor cell population leading to tumor recurrence.

Patients and methods: Mayo 39 and Mayo 59 xenograft lines were cultured and xenografts were maintained. Subcutaneous xenograft lines were serially passaged in nude mice to generate subcutaneous xenografts. Xenografts were implanted in 6-8 week old nude mice. Once tumors reached a substantial size (150 mm3), mice were randomly divided into 4 groups: 1) control vehicle, 2) Crizotinib (crizo), 3) Erlotinib (erlot), or 4) Crizotinib + Erlotinib, (n = 5 per group).

Results: Crizotinib (c-Met pathway inhibitor) and Erlotinib (EGFR pathway inhibitor) in combination significantly inhibited tumor growth, phospho-EGFRvIII, phospho-Met, phospho-AKT, phospho-MAPK, and neurosphere growth in Mayo 39 and Mayo 59 primary GBM subcutaneous xenografts. The expression of the stem cell markers Nestin, Musashi, Olig 2 and Sox2 were also significantly down-regulated by c-Met inhibition, but no additive down-regulation was seen by co-treatment with Erlotinib.

Conclusions: These results are consistent with and corroborate our previous findings demonstrating that targeting these two parallel pathways with c-Met and EGFR inhibitor therapy provides substantial anti-tumor activity in glioblastoma models.

Keywords: Crizotinib; Epidermal growth factor receptor; Erlotinib; Glioblastoma; Primary xenograft; c-Met.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / pathology
  • Crizotinib / pharmacology*
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / pharmacology*
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Heterografts / drug effects
  • Humans
  • Mice, Nude
  • Neoplasm Recurrence, Local / drug therapy
  • Proto-Oncogene Proteins c-met / drug effects*


  • Antibodies, Monoclonal
  • Crizotinib
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met