CIP2A pathway involved in erlotinib response

Jul 16 2014

By Laura Cowen, medwireNews Reporter

Researchers have identified a novel mechanism, involving the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway, which mediates the anti-tumour effects of erlotinib in non-small-cell lung cancer (NSCLC) cells without epidermal growth factor receptor (EGFR) mutations.

Chong-Jen Yu (National Taiwan University Hospital, Taipei) and colleagues explain that “[a]lthough NSCLC patients with EGFR-mutation respond well to EGFR inhibitors, such as erlotinib, some NSCLC patients without EGFR mutations also show favorable response.”

This suggests that there “may be mechanism(s) other than the EGFR-pathway” mediating the tumouricidal effects of erlotinib, say Yu and team. Indeed, they have previously shown that erlotinib prevents the growth of hepatocellular carcinoma cells by inhibiting the CIP2A pathway.

They therefore investigated whether similar mechanisms are present in NSCLC cells.

The researchers found that treatment with erlotinib (0, 1, 5, 10 and 20 μg) induced significant cell death and apoptosis in NSCLC cell lines H358 and H441 in a dose- and time-dependent manner, but had no significant effect in H460 and H549 cells.

Increased caspase 3 activity and cleavage of pro-caspase 9 and poly ADP ribose polymerase following 48 hours of treatment with erlotinib confirmed that apoptosis was occurring in the H358 and H441 cells, with no such increases observed in the H460 and H549 cells.

The team then investigated the role of CIP2A in the sensitivity to erlotinib and found that CIP2A protein expression, as well as protein kinase B (AKT) phosphorylation, was decreased, and protein phosphatase 2A activity was increased, in the H358 cells but not in the H460 cells.

Furthermore, overexpression of CIP2A and AKT partially protected the sensitive H358 cells from erlotinib-induced apoptosis, whereas knockdown of CIP2A gene expression by small interfering RNA enhanced erlotinib-induced apoptosis in the resistant H460 cells.

These findings indicate that CIP2A expression status and AKT activation are “important in regulating the apoptotic effect of erlotinib in NSCLC cells”, Yu and co-authors remark. They add that the findings may “explain the poor prognosis in patients whose lung tumors overexpressed CIP2A.”

The researchers also showed that treatment with erlotinib significantly inhibited tumour growth in mice implanted with H358 xenografts, reducing tumour sizes to approximately one-fifth of those observed in mice that did not receive erlotinib.

Writing in Lung Cancer, the researchers conclude that “[t]he expression status of CIP2A could be a molecular determinant of the sensitivity of NSCLC cells to erlotinib.”

They add: “Development of novel therapies targeting CIP2A would increase our therapeutic options for patients with NSCLC.”

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