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

C. Rory Goodwin, Prakash Rath, Olutobi Oyinlade, Hernando Lopez-Bertoni, Salman Mughal, Shuli Xia, Yunqing Li, Harsharan Kaur, Xin Zhou, A. Karim Ahmed, Sandra Ho, Alessandro Olivi, Bachchu Lal

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)26-33
Number of pages8
JournalClinical Neurology and Neurosurgery
Volume171
DOIs
StatePublished - Aug 1 2018

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Glioblastoma
Heterografts
Growth
Epidermal Growth Factor Receptor
Neoplasms
Receptor Protein-Tyrosine Kinases
Nude Mice
Erlotinib Hydrochloride
crizotinib
epidermal growth factor receptor VIII
Nestin
Stem Cells
Therapeutics
Down-Regulation
Recurrence
Cell Line
Control Groups

Keywords

  • c-Met
  • Crizotinib
  • Epidermal growth factor receptor
  • Erlotinib
  • Glioblastoma
  • Primary xenograft

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts. / Goodwin, C. Rory; Rath, Prakash; Oyinlade, Olutobi; Lopez-Bertoni, Hernando; Mughal, Salman; Xia, Shuli; Li, Yunqing; Kaur, Harsharan; Zhou, Xin; Ahmed, A. Karim; Ho, Sandra; Olivi, Alessandro; Lal, Bachchu.

In: Clinical Neurology and Neurosurgery, Vol. 171, 01.08.2018, p. 26-33.

Research output: Contribution to journalArticle

Goodwin, C. Rory ; Rath, Prakash ; Oyinlade, Olutobi ; Lopez-Bertoni, Hernando ; Mughal, Salman ; Xia, Shuli ; Li, Yunqing ; Kaur, Harsharan ; Zhou, Xin ; Ahmed, A. Karim ; Ho, Sandra ; Olivi, Alessandro ; Lal, Bachchu. / Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts. In: Clinical Neurology and Neurosurgery. 2018 ; Vol. 171. pp. 26-33.
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AU - Oyinlade, Olutobi

AU - Lopez-Bertoni, Hernando

AU - Mughal, Salman

AU - Xia, Shuli

AU - Li, Yunqing

AU - Kaur, Harsharan

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AU - Ahmed, A. Karim

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AU - Lal, Bachchu

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