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

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.

Hedgehog-responsive PDGFRa(+) fibroblasts maintain a unique pool of alveolar epithelial progenitor cells during alveologenesis

“…The function of individual inhibitors was validated as shown in Figure S10 . Blocking HGF with capmatinib, an ATP-competitive inhibitor of c-MET ( Clement et al, 2020 ; Kong et al, 2020 ; Oh et al, 2021 ), while dramatically reducing organoid size, had a moderate impact on colony-forming efficiency (CFE) ( Figure 6A , a8 and a9 ). Inhibition of BMP by GREM2 ( Tanwar et al, 2014 ) had no impact on CFE but reduced the organoid size, suggesting its activity may be more related to pAT2 proliferation ( Figure 6A , a8 and a9 ).…”

LMNA Reduced Acquired Resistance to Erlotinib in NSCLC by Reversing the Epithelial–Mesenchymal Transition via the FGFR/MAPK/c-fos Signaling Pathway

“…EMT is a dynamic process that affects many malignancies, including drug resistance. Accumulating evidence has highlighted that EMT has long been associated with acquired resistance to EGFR-TKIs in NSCLC [ 19 , 20 , 21 , 22 ], but the mechanisms underlying the acquired resistance to EGFR-TKIs dependent on EMT remained poorly understood. In the present study, an erlotinib-resistant HCC827/ER cell line was established by treating EGFR-mutated HCC827 cells with increasing doses of erlotinib until resistance was achieved at 5 μM erlotinib.…”

“…In previous studies, FGFR signaling has been associated with resistance to EGFR-TKIs caused by EMT [ 30 , 31 , 32 ]. By blocking both EGFR and FGFR, acquired resistance can be inhibited through blocking of the development of EMT in NSCLC with EGFR mutations [ 22 , 31 ]. In this study, we found that FGFR signaling was activated, resulting in acquired resistance of HCC827/ER cells and HCC827/sh LMNA cells to erlotinib.…”

Discovery of a small molecule ligand of FRS2 that inhibits invasion and tumor growth

“…ALK is overexpressed in ovarian cancer and associated with an aggressive, metastatic phenotype [44,45]. Finally, FRS2 inhibition could also be suitable as a combinatorial therapy strategy in KRAS-driven tumors with acquired MEKi resistance, which are sensitive to FRS2 depletion [46], or to bypass FGFR-driven resistance to epidermal growth factor receptor (EGFR) [47] or mesenchymal epithelial transition (MET) inhibition [48].…”