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Mol Oncol. 2016 Apr;10(4):601-9. doi: 10.1016/j.molonc.2015.11.007. Epub 2015 Nov 24.

EMT is associated with, but does not drive resistance to ALK inhibitors among EML4-ALK non-small cell lung cancer.

Author information

1
Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA.
2
Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC, 20007, USA. Electronic address: gg496@georgetown.edu.

Abstract

ALK gene fusion occurs in approximately 3-7% of non-small cell lung cancer (NSCLC). For patients with ALK positive NCSLC, crizotinib and ceritinib are FDA approved ALK inhibitors, however, patients inevitably acquire resistance to such therapies typically within one to two years. Interrogation of in vitro ALK-positive NSCLC cell line models of acquired resistance to first and second-generation ALK inhibitors revealed acquired epithelial-to-mesenchymal transition (EMT) mechanisms. Here we demonstrated that knockdown of upregulated mesenchymal markers in acquired resistant lines decreased the invasive and migratory capabilities of the cells, however, it did not restore sensitivity to ALK inhibitors. Removing drug for 5 weeks from H3122 cell line that acquired resistance to ceritinib restored its sensitivity to ceritinib. In addition, HSP90 inhibitors ganetespib and 17-AAG were potent in inducing cell death in cell lines resistant to crizotinib and ceritinib. Taken together, EMT does not drive resistance to ALK inhibitors and HSP90 inhibition demonstrates more efficacy when further ALK inhibition may not. This study warrants more exploration of HSP90 inhibitors for ALK-positive patients who progress on 1st and 2nd line ALK inhibitor therapy.

KEYWORDS:

ALK-positive NSCLC; Ceritinib; Epithelial–mesenchymal transition; HSP90 inhibition; Resistance

PMID:
26639656
PMCID:
PMC5423150
DOI:
10.1016/j.molonc.2015.11.007
[Indexed for MEDLINE]
Free PMC Article

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