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

Publication ,  Journal Article
Goodwin, CR; Rath, P; Oyinlade, O; Lopez, H; Mughal, S; Xia, S; Li, Y; Kaur, H; Zhou, X; Ahmed, AK; Ho, S; Olivi, A; Lal, B
Published in: Clin Neurol Neurosurg
August 2018

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.

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Published In

Clin Neurol Neurosurg

DOI

EISSN

1872-6968

Publication Date

August 2018

Volume

171

Start / End Page

26 / 33

Location

Netherlands

Related Subject Headings

  • Proto-Oncogene Proteins c-met
  • Neurology & Neurosurgery
  • Neoplasm Recurrence, Local
  • Mice, Nude
  • Humans
  • Heterografts
  • Glioblastoma
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Crizotinib
 

Citation

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Goodwin, C. R., Rath, P., Oyinlade, O., Lopez, H., Mughal, S., Xia, S., … Lal, B. (2018). Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts. Clin Neurol Neurosurg, 171, 26–33. https://doi.org/10.1016/j.clineuro.2018.02.041
Goodwin, C Rory, Prakash Rath, Olutobi Oyinlade, Hernando Lopez, Salman Mughal, Shuli Xia, Yunqing Li, et al. “Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts.Clin Neurol Neurosurg 171 (August 2018): 26–33. https://doi.org/10.1016/j.clineuro.2018.02.041.
Goodwin CR, Rath P, Oyinlade O, Lopez H, Mughal S, Xia S, et al. Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts. Clin Neurol Neurosurg. 2018 Aug;171:26–33.
Goodwin, C. Rory, et al. “Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts.Clin Neurol Neurosurg, vol. 171, Aug. 2018, pp. 26–33. Pubmed, doi:10.1016/j.clineuro.2018.02.041.
Goodwin CR, Rath P, Oyinlade O, Lopez H, Mughal S, Xia S, Li Y, Kaur H, Zhou X, Ahmed AK, Ho S, Olivi A, Lal B. Crizotinib and erlotinib inhibits growth of c-Met+/EGFRvIII+ primary human glioblastoma xenografts. Clin Neurol Neurosurg. 2018 Aug;171:26–33.
Journal cover image

Published In

Clin Neurol Neurosurg

DOI

EISSN

1872-6968

Publication Date

August 2018

Volume

171

Start / End Page

26 / 33

Location

Netherlands

Related Subject Headings

  • Proto-Oncogene Proteins c-met
  • Neurology & Neurosurgery
  • Neoplasm Recurrence, Local
  • Mice, Nude
  • Humans
  • Heterografts
  • Glioblastoma
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Crizotinib