STAT3 gene mutation in NSCLC independent of typical oncogenic driver mutations

Looyenga BD. PLoS One. 2012;doi:10.1371/journal.pone.0030820.

Issue: April 10, 2012

In several non–small cell lung cancer cell lines, the STAT3 gene was activated by the JAK2 protein, which may cause resistance to drugs intended to target these mutations, according to study results published in the Public Library of Science (PLoS) ONE.

To identify signaling pathways that did not respond to targeted tyrosine kinase inhibitors, researchers treated epidermal growth factor receptor mutant cell lines with the molecule inhibitor and assayed multiple signaling pathways using a phosphoprotein array.

Although EGFR and several of its effectors — including PI3K/mTOR and ERK — were deactivated by the erlotinib treatment, researchers observed that STAT3 remained activated in both cell lines after erlotinib treatment. Further analysis of these pathways confirmed the findings of the phosphoprotein array, indicating that STAT3 is activated independent of an EGFR in these NSCLC cells.

“This suggests that there may be a potential role for combination therapy, so you have a better chance of knocking out select NSCLC tumors driven by STAT3-JAK2, or keeping it at bay,” Glen Weiss, MD, director of Thoracic Oncology at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, said in a press release.

Additionally, inhibition of EGFR with erlotinib failed to change the nuclear localization of STAT3 in one of the mutant cell lines, indicating that STAT3 remained active and appropriately localized in the absence of signaling by EGFR.

“JAK2-STAT3 signaling plays crucial roles in tumor-cell behavior that may not be effectively inhibited by drugs that selectively target these mutations,” Jeff MacKeigan, PhD, head of the Van Andel Research Institute’s Laboratory of Systems Biology, said in a press release.

Disclosure: The researchers report no relevant financial disclosures.

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