Oncotarget

Research Papers:

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

Carles Codony-Servat, Jordi Codony-Servat, Niki Karachaliou, Miguel Angel Molina, Imane Chaib, Jose Luis Ramirez, Maria de los Llanos Gil, Flavio Solca, Trever G. Bivona and Rafael Rosell _

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Oncotarget. 2017; 8:47305-47316. https://doi.org/10.18632/oncotarget.17625

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Abstract

Carles Codony-Servat1, Jordi Codony-Servat1, Niki Karachaliou2, Miguel Angel Molina1, Imane Chaib3, Jose Luis Ramirez3,4, Maria de los Llanos Gil5, Flavio Solca6, Trever G. Bivona7 and Rafael Rosell3,4

1Pangaea Oncology, Barcelona, Spain

2Instituto Oncológico Dr Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain

3Institut d’Investigació en Ciències Germans Trias i Pujol, Badalona, Spain

4Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain

5Instituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain

6Boehringer Ingelheim RCV GmbH and Co. KG, Vienna, Austria

7UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States

Correspondence to:

Rafael Rosell, email: rrosell@iconcologia.net

Keywords: lung cancer, EGFR, STAT3, afatinib, resistance

Received: March 07, 2017     Accepted: April 20, 2017     Published: May 04, 2017

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.


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