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

Oncotarget
Carles Codony-ServatRafael Rosell

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 Hai...Continue Reading

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Citations

Aug 7, 2018·Expert Review of Anticancer Therapy·Ilaria AttiliRafael Rosell
Apr 11, 2018·Therapeutic Advances in Medical Oncology·Ilaria AttiliRafael Rosell
Aug 15, 2019·Expert Review of Respiratory Medicine·Niki KarachaliouRafael Rosell
Nov 2, 2019·The Journal of Clinical Investigation·Emilie Bousquet MurAntonio Maraver
Jun 21, 2019·Molecular Cancer Therapeutics·Judith BossenThomas Roeder
May 29, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Liuxin WangXueqing Zhang
Apr 9, 2021·Investigational New Drugs·Xiaoping SongJing Li
Jun 3, 2021·International Journal of Molecular Sciences·Helena OliveresJoan Maurel
Jun 5, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xueting CaiPeng Cao
Aug 11, 2021·British Journal of Cancer·Rafael RosellMariacarmela Santarpia
Mar 7, 2018·The Lancet Oncology·Rafael Rosell, Niki Karachaliou

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Methods Mentioned

BETA
reverse transcription-PCR
flow cyrometry
flow cytometry
electrophoresis
FACS

Software Mentioned

Primer Express

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