Oncotarget

Research Papers:

Molecular mechanism of action and potential biomarkers of growth inhibition of synergistic combination of afatinib and dasatinib against gefitinib-resistant non-small cell lung cancer cells

Miao Wang and Alex Yuang-chi Chang _

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Oncotarget. 2018; 9:16533-16546. https://doi.org/10.18632/oncotarget.24814

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Abstract

Miao Wang1 and Alex Yuang-Chi Chang1,2

1Department of Oncology, Johns Hopkins Singapore International Medical Center, Singapore

2Department of Oncology, Johns Hopkins University, Baltimore, MD, USA

Correspondence to:

Alex Yuang-Chi Chang, email: achang10@jhmi.edu

Keywords: molecular mechanism; growth inhibition; synergistic combination; gefitinib resistance; non-small cell lung cancer

Received: December 19, 2017     Accepted: February 28, 2018     Published: March 27, 2018

ABSTRACT

Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) is the first choice of treatment for advanced non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, single agent usually has limited efficacy due to heterogeneous resistant mechanisms of cancer cells. Thus drug combination therapy would offer more benefits by synergistic interactions and avoidance of resistance emergence. In this study, we selected 8 NSCLC cell lines with different genetic characteristics as research models to investigate the efficacy of 4 agents (gefitinib, cetuximab, afatinib and dasatinib) and their combinations. As a single agent, both afatinib and dasatinib showed more inhibition against cell proliferation than gefitinib and cetuximab. Afatinib combined with dasatinib demonstrated significantly high efficacy against 7 gefitinib-resistant NSCLC cell lines. Moreover, it reversed the resistance to the 4 studied single agents in PTEN mutated NSCLC cells. By studying the activity of EGFR, Src and their downstream signalling pathways including PI3K/PTEN/Akt, Ras/Raf/MEK/ERK, Src/FAK and JAK/Stat, we demonstrated the synergistic interaction between afatinib and dasatinib was not only due to their blockage of different signalling pathways but also the complemental inhibition of the related signalling molecules such as Stat3. We also found that the level of Src, Stat3, and MAPK may be useful biomarkers predicating synergism between afatinib and dasatinib for the treatment of gefitinib-resistant NSCLC cells.


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