Dataset Information


Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC).

ABSTRACT: Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory. Afatinib has great activity in gefitinib-sensitive as well as in gefitinib-resistant EGFR mutant NSCLC cell lines. However, afatinib therapy causes phosphorylation of STAT3 tyrosine 705 (pSTAT3Tyr705) and elevation of STAT3 and RANTES mRNA levels. The combination of afatinib with TPCA-1 (a STAT3 inhibitor) ablated pSTAT3Tyr705 and down-regulated STAT3 and RANTES mRNA levels with significant growth inhibitory effect in both gefitinib-sensitive and gefitinib-resistant EGFR mutant NSCLC cell lines. Aldehyde dehydrogenase positive (ALDH+) cells were still observed with the combination at the time that Hairy and Enhancer of Split 1 (HES1) mRNA expression was elevated following therapy. Although the combination of afatinib with STAT3 inhibition cannot eliminate the potential problem of a remnant cancer stem cell population, it represents a substantial advantage and opportunity to further prolong progression free survival and probably could increase the response rate in comparison to the current standard of single therapy.

SUBMITTER: Codony-Servat C 

PROVIDER: S-EPMC5564566 | BioStudies | 2017-01-01

SECONDARY ACCESSION(S): 10.18632/oncotarget.17625

REPOSITORIES: biostudies

Similar Datasets

2018-01-01 | S-EPMC5893260 | BioStudies
2016-01-01 | S-EPMC6003619 | BioStudies
2014-01-01 | S-EPMC4119578 | BioStudies
1000-01-01 | S-EPMC4499885 | BioStudies
2019-01-01 | S-EPMC6815809 | BioStudies
2021-01-01 | S-EPMC7826488 | BioStudies
2005-01-01 | S-EPMC553328 | BioStudies
2015-01-01 | S-EPMC4467405 | BioStudies
2016-01-01 | S-EPMC4724821 | BioStudies
2013-01-01 | S-EPMC3601073 | BioStudies