ABSTRACT
EGFR inhibitors (EGFRi) are standard-of-care treatments administered to patients with non-small cell lung cancer (NSCLC) that harbor EGFR alterations. However, development of resistance posttreatment remains a major challenge. Multiple mechanisms can promote survival of EGFRi-treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, the mechanisms involved in bypass signaling activation are understudied and require further elucidation. In this study, we identify that loss of an epigenetic factor, lysine methyltransferase 5C (KMT5C), drives resistance of NSCLC to multiple EGFRis, including erlotinib, gefitinib, afatinib, and osimertinib. KMT5C catalyzed trimethylation of histone H4 lysine 20 (H4K20), a modification required for gene repression and maintenance of heterochromatin. Loss of KMT5C led to upregulation of an oncogenic long noncoding RNA, LINC01510, that promoted transcription of the oncogene MET, a component of a major bypass mechanism involved in EGFRi resistance. These findings underscore the loss of KMT5C as a critical event in driving EGFRi resistance by promoting a LINC01510/MET axis, providing mechanistic insights that could help improve NSCLC treatment. SIGNIFICANCE: Dysregulation of the epigenetic modifier KMT5C can drive MET-mediated EGFRi resistance, implicating KMT5C loss as a putative biomarker of resistance and H4K20 methylation as a potential target in EGFRi-resistant lung cancer.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Histone-Lysine N-Methyltransferase , Lung Neoplasms , Proto-Oncogene Proteins c-met , RNA, Long Noncoding , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Histone-Lysine N-Methyltransferase/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lysine/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/genetics , RNA, Long Noncoding/genetics , Up-RegulationABSTRACT
A cold atmospheric pressure plasma device was developed using two parallel plates of Low Temperature Co-fired Ceramic with embedded electrodes. The 2.4 cm wide by 1 mm deep plasma discharge operates at 20 kHz with a 2-5 kV AC drive signal across a 0.25 mm gap. Mixed Argon/oxygen plasmas were directed between the plates to flow toward a bacterial biofilm sample for treatment. Results showed that at 4-5 kV the plasma etched away a bacterial biofilm on glass in 10 minutes. In addition, we showed that short plasma treatments rapidly killed biofilm resident bacteria with ED90 values of <15 s.
