Oncotarget

Research Papers:

IGF1R depletion facilitates MET-amplification as mechanism of acquired resistance to erlotinib in HCC827 NSCLC cells

Dianna Hussmann, Anne Tranberg Madsen, Kristine Raaby Jakobsen, Yonglun Luo, Boe Sandahl Sorensen and Anders Lade Nielsen _

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Oncotarget. 2017; 8:33300-33315. https://doi.org/10.18632/oncotarget.16350

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Abstract

Dianna Hussmann1, Anne Tranberg Madsen2, Kristine Raaby Jakobsen1,2, Yonglun Luo1, Boe Sandahl Sorensen2 and Anders Lade Nielsen1

1Department of Biomedicine, Aarhus University, Aarhus, Denmark

2Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark

Correspondence to:

Anders Lade Nielsen, email: aln@biomed.au.dk

Keywords: NSCLC, IGF1R, EGFR-TKI, EMT, MET

Received: November 02, 2016     Accepted: February 22, 2017     Published: March 18, 2017

ABSTRACT

EGFR-mutated non-small cell lung cancer patients experience relapse within 1-2 years of treatment with EGFR-inhibitors, such as erlotinib. Multiple resistance mechanisms have been identified including secondary EGFR-mutations, MET-amplification, and epithelial-mesenchymal transition (EMT). Previous studies have indicated a role of Insulin-like growth factor 1 receptor (IGF1R) in acquired resistance to EGFR-directed drugs as well as in EMT. In the present study, we have investigated the involvement of IGF1R in acquired high-dose erlotinib resistance in the EGFR-mutated lung adenocarcinoma cell line HCC827. We observed that IGF1R was upregulated in the immediate response to erlotinib and hyperactivated in erlotinib resistant HCC827 cells. Resistant cells additionally acquired features of EMT, whereas MET-amplification and secondary EGFR-mutations were absent. Using CRISPR/Cas9, we generated a HCC827(IGFR1−/−) cell line and subsequently investigated resistance development in response to high-dose erlotinib. Interestingly, HCC827(IGFR1−/−) cells were now observed to specifically amplify the MET gene. Additionally, we observed a reduced level of mesenchymal markers in HCC827(IGFR1−/−) indicating an intrinsic enhanced epithelial signature compared to HCC827 cells. In conclusion, our data show that IGF1R have an important role in defining selected resistance mechanisms in response to high doses of erlotinib.


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