CRIPTO1 role in the resistance of TKI elucidated -
By Lynda Williams, first medwireNews Problem
Overexpression of CRIPTO1 may explain inhibitor intrinsic tyrosine kinase resistance (TKI) in about 10% of patients with non-small cell lung cancer (NSCLC) and receiver endothelial growth factor ( EGFR ) mutations, research indicates.
CRIPTO1 expression has been linked to the induction of epithelial cells to mesenchymal transition, the proliferation and cell migration and invasion by a CBC channel. And these biological responses are associated with resistance to targeted cancer drugs, said Giuseppe Giaccone, of Georgetown University in Washington DC, USA, and colleagues.
The researchers examined the expression of CRIPTO1 in 21 NSCLC tissue samples and found 15 expressed the protein, which also had 14 SRC phosphorylation.
Moreover, when EGFR -mutated NSCLC cell lines were engineered to express CRIPTO1, they were found to have a significantly higher value for IC TKI erlotinib and dacomitinib the lines control cells.
however, which induces the expression of CRIPTO1 in wild type EGFR cell lines had no impact on their sensitivity to TKIs. And sensitivity to cisplatin and paclitaxel did not differ significantly between cells expressing CRIPTO1 and controls, the researchers report in the Journal of Clinical Investigation .
In addition, when the researchers examined the CBC signaling pathway in NSCLC cells EGFR cell lines expressing -mutant CRIPTO1 SRC had increased mRNA and protein compared to controls, and SRC that phosphorylated AKT and MEK, while no effect was observed for wild type EGFR cell lines.
Similarly, the expression of CRIPT01 has been associated with the induction of EMT in NSCLC cell lines, especially in the mutant EGFR lines.
Finally, the researchers found that resistance to erlotinib is mediated by the CBC and the expression of CRIPTO1 may mediate its control SCR via downregulation of miR-205.
"In conclusion, we demonstrate that overexpression CRIPTO1 potentially represents a new intrinsic EGFR TKI resistance mechanism in NSCLC-host sensitizing EGFR mutations," Giaccone et al write.
"Our study suggests cotargeting EGFR and CBC as a rational approach for the potential treatment of erlotinib-resistant, positive CRIPTO1, mutated NSCLC patients EGFR."
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