CRIPTO1 role in TKI resistance elucidated

Overexpression of CRIPTO1 may explain intrinsic tyrosine kinase inhibitor (TKI) resistance in around 10% of patients with non-small-cell lung cancer (NSCLC) and endothelial growth factor receptor (EGFR) mutations, research indicates.

CRIPTO1 expression has been linked to the induction of epithelial to mesenchymal transition, as well cell proliferation, migration and invasion through a SRC pathway. And these biological responses are associated with resistance to targeted cancer drugs, explain Giuseppe Giaccone, from Georgetown University in Washington DC, USA, and co-workers.

The researchers examined CRIPTO1 expression in 21 NSCLC tissue samples and found 15 expressed the protein, 14 of which also had SRC phosphorylation.

Moreover, when EGFR-mutated NSCLC cell lines were altered to express CRIPTO1, they were found to have a significantly higher IC value for the TKIs erlotinib and dacomitinib than the control cell lines.

By contrast, inducing 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 significantly differ between the CRIPTO1 expressing cells and controls, the researchers report in the Journal of Clinical Investigation.

Furthermore, when the researchers examined the SRC signalling path in NSCLC cells, EGFR-mutant cell lines expressing CRIPTO1 had increased SRC mRNA and protein levels compared with controls, as well as phosphorylated SRC, AKT and MEK, whereas no such effect was noted for wild-type EGFR cell lines.

Similarly, CRIPT01 expression was associated with induction of EMT in NSCLC cell lines, especially among mutant EGFR lines.

Finally, the researchers found that erlotinib resistance is mediated by SRC and that CRIPTO1 expression may mediate its control of SCR via downregulation of miR-205.

“In conclusion, we demonstrate that CRIPTO1 overexpression potentially represents a novel mechanism of intrinsic EGFR-TKI resistance in NSCLC-harboring sensitizing EGFR mutations”, Giaccone et al write.

“Our study suggests cotargeting of EGFR and SRC as a potential rational approach to the treatment of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC patients.”

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