MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells

Abstract

Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30–40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI.

Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment inEGFR-Mutant Non–Small Cell Lung Cancer Cells

“…Among these three METamplified resistant cell lines, combined treatment with osimertinib and crizotinib was only effective in one of the cell lines. The detailed mechanisms underlying these results remain unknown, but they are consistent with a previous report that MET gene amplification and MET receptor activation are insufficient to predict a positive response of NSCLC cells to combined treatment with MET and EGFR inhibitors (44).…”

Combined treatment with vitamin C and methotrexate inhibits triple-negative breast cancer cell growth by increasing H2O2 accumulation and activating caspase-3 and p38 pathways

“…The results indicated that vitamin C is not efficient in enhancing MTX-induced cytotoxicity in tarceva-resistant TNBC cells. Previously, many studies showed that tarcevaresistant cells have EGFR gene mutations or additional bypass signaling pathways to activate downstream of EGFR (65,66). These mutation genes and bypass pathways are important factors for cell proliferation with EGFR inhibitor treatment.…”

Tumor‑released lncRNA H19 promotes gefitinib resistance via packaging into exosomes in non‑small cell lung cancer

“…The human NSCLC cell lines HCC827 and HCC4006, which harbor EGFR activating mutations ( 16 , 17 ), were purchased from the Chinese Academy of Sciences (Shanghai, China). Both cell lines were cultured in RPMI-1640 medium (BioWhittaker ® ; Lonza Group, Ltd., Basel, Switzerland) supplemented with 10 mM HEPES, 1 mM L-glutamine, 100 U/ml penicillin/streptomycin (BioWhittaker ® ; Lonza Group) and heat inactivated 10% fetal bovine serum (FBS; Gibco; Thermo Fisher Scientific, Inc.) and grown at 37°C in a 5% CO 2 atmosphere.…”