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

2017; Impact Journals LLC; Volume: 8; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.17625

1949-2553

Carles Codony, Jordi Codony‐Servat, Niki Karachaliou, Miguel Ángel Molina‐Vila, Imane Chaib, José Luis Ramírez, María de los Llanos Gil, Flavio Solca, Trever G. Bivona, Rafael Rosell,

Cancer Mechanisms and Therapy

// Carles Codony-Servat 1 , Jordi Codony-Servat 1 , Niki Karachaliou 2 , Miguel Angel Molina 1 , Imane Chaib 3 , Jose Luis Ramirez 3, 4 , Maria de los Llanos Gil 5 , Flavio Solca 6 , Trever G. Bivona 7 and Rafael Rosell 3, 4 1 Pangaea Oncology, Barcelona, Spain 2 Instituto Oncológico Dr Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain 3 Institut d'Investigació en Ciències Germans Trias i Pujol, Badalona, Spain 4 Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain 5 Instituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain 6 Boehringer Ingelheim RCV GmbH and Co. KG, Vienna, Austria 7 UCSF 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 (pSTAT3 Tyr705 ) and elevation of STAT3 and RANTES mRNA levels. The combination of afatinib with TPCA-1 (a STAT3 inhibitor) ablated pSTAT3 Tyr705 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.