MET inhibition downregulates DR4 expression in MET-amplified lung cancer cells with acquired resistance to EGFR inhibitors through suppressing AP-1-mediated transcription

• DOI: 10.1016/j.neo.2021.06.006
• Publication Date: 2021-07-04T08:51:49Z
• Authors: Liang Deng; Karin A. Vallega; Shuo Zhang; Puyu Shi; Shi-Yong Sun
• Keywords: 0301 basic medicine; Lung Neoplasms; Cell Survival; MAP Kinase Signaling System; EGFR-TKIs; Models, Biological; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; DR4; Protein Kinase Inhibitors; RC254-282; Original Research; Protein Stability; Gene Amplification; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Proto-Oncogene Proteins c-met; 3. Good health; ErbB Receptors; Gene Expression Regulation, Neoplastic; Transcription Factor AP-1; Disease Models, Animal; Receptors, TNF-Related Apoptosis-Inducing Ligand; Drug Resistance, Neoplasm; MET; Heterografts; Acquired resistance; Lung cancer

Death receptor 4 (DR4) is a cell surface protein that generally thought to mediate apoptosis upon binding its ligand named TRAIL. However, contribution resistance has also been reported. MET (or c-MET) gene amplification represents an important mechanism for acquired EGFR tyrosine kinase inhibitors (EGFR-TKIs) against mutant non-small lung cancer (NSCLC). This study focuses on demonstrating the impact of inhibition DR4 modulation in MET-amplified NSCLC lines and underlying mechanisms. Several decreased levels HCC827 resistant EGFR-TKIs with no or limited effects modulating DR5 levels, while increasing parental cells other lines. did not affect stability, but mRNA suppression AP-1-dependent promoter transactivation. Moreover, these suppressed ERK c-Jun phosphorylation accompanied decreasing levels. Hence, it likely downregulates expression through suppressing AP-1-mediated transcription. Osimertinib combined synergistically induces augmented reduction both vitro vivo. Furthermore, TRAIL enhanced killing HCC827/AR cells, cells. These data collectively suggest may possess unrecognized anti-apoptotic function, contributing under given conditions.