Moreover, the identification of EGFR as a transcriptional regulator of PTHLH in neuroblastoma provides a novel therapeutic opportunity to promote a less aggressive tumor phenotype through irreversible inhibition of EGFR tyrosine kinase activity.
Vasoactive intestinal polypeptide receptor 1 (VPAC1) and epidermal growth factor receptor (EGFR) are associated with signal transduction pathways relevant to neuroblastoma, cancer of breast, prostate and lungs.
In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in <sup>EGFR</sup>EDV<sup>TM</sup><sub>Dox</sub>-treated animals compared to control, doxorubicin, or non-EGFR EDV<sup>TM</sup><sub>Dox</sub> There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDV<sup>TM</sup><sub>Dox</sub> Moreover, overall survival was increased in neuroblastoma mice treated with <sup>EGFR</sup>EDV<sup>TM</sup><sub>Dox</sub> (<i>P</i> < 0007) compared to control.
Taken together, these results show that afatinib inhibits neuroblastoma growth both in vitro and in vivo by suppressing EGFR-mediated PI3K/AKT/mTOR signaling.
Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants.
Clinically, EGFR inhibitors are ineffective as single agent compounds in patients with recurrent NB, likely due to this transferred survival dependence to Bcl(-)2.
The discovery of anti-EGFR resistance in the setting of Kirsten rat sarcoma viral oncogene (KRAS) and more recently, neuroblastoma RAS viral oncogene (NRAS) mutations in CRC has changed the focus of therapy for metastatic disease to one based on the molecular characteristics of the tumor.
EGFR expression and gene mutation were studied by reversetranscriptase-polxmerase chain reacting, fluorescence-activated cell sorting and gene sequencing in six neuroblastoma cell lines.
The EGFR-targeted antibody and growth factor toxins scFv(14E1)- Pseudomonas exotoxin A (ETA) and TGF-alpha-ETA exerted anti-cancer effects in neuroblastoma cell lines that were insensitive to cetuximab or EGFR tyrosine kinase inhibitors.
Here, we show that TGFalpha, a known activator of Ras signaling, can drive cell proliferation and at the same time induce the expression of the Notch target Hes-1 in the neuroblastoma cell line SK-N-BE(2)c. The up-regulation of Hes-1 occurred both at the transcriptional and protein levels and by use of EGFR and MEK inhibitors we could show that the Hes-1 response was dependent on activation of the MAP kinase ERK.
Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma.