Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Michelle Simone Clement; Kristine Raaby Gammelgaard; Anders Lade Nielsen; Boe Sandahl Sorensen

doi:10.21037/tlcr-20-522

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of MET-amplified EGFR-TKI resistant non-small cell lung cancer cells

Transl Lung Cancer Res. 2020 Oct;9(5):1904-1914. doi: 10.21037/tlcr-20-522.

Authors

Michelle Simone Clement¹, Kristine Raaby Gammelgaard², Anders Lade Nielsen², Boe Sandahl Sorensen¹

Affiliations

¹ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
² Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Abstract

Background: Tyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC). MET amplification drives resistance to EGFR-TKIs in 5-20% of initially sensitive.

Egfr: mutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment.

Methods: To investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in EGFR-mutated HCC827 cells with MET amplification-mediated erlotinib resistance. These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance.

Results: In all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1. Furthermore, FGFR1 expression was increased in all MET-TKI resistant cell lines and four out of the six resistant cell lines had increased sensitivity to FGFR inhibition, indicating FGFR1-mediated bypass signaling.

Conclusions: EMT is common in the development of sequential EGFR-TKI and MET-TKI resistance in NSCLC cells. Our findings contribute to the evidence of EMT as a common TKI resistance mechanism.

Keywords: MET receptor tyrosine kinase; Non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); epithelial-to-mesenchymal transition (EMT); tyrosine kinase inhibitor resistance.