Journal
ONCOTARGET
Volume 8, Issue 20, Pages 33300-33315Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16350
Keywords
NSCLC; IGF1R; EGFR-TKI; EMT; MET
Categories
Funding
- Fonden til Laegevidenskabens Fremme
- Harboe Fonden
- Arvid Nilssons Fond
- Else og Mogens Wedell-Wedellsborgs Fond
- Krista og Viggo Petersens Fond
- Familien Hede Nielsens Fond
- Direktor Jacob Madsen & Hustru Olga Madsens Fond
- Fabrikant Einar Willumsens Mindelegat
- Marie og Borge Kroghs Fond
- The Graduate School of Health, Aarhus University, DK
- The Danish Cancer Society [R141-A8898] Funding Source: researchfish
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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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