Loss of SUV420H2 promotes EGFR inhibitor resistance in NSCLC through upregulation of MET via LINC01510

Abstract

Epidermal growth factor receptor 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 within a year post-treatment 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, mechanisms involved in bypass track activation are understudied, and in a subset of cases the mechanisms are unknown. The findings from this study identified an epigenetic factor, SUV420H2 that when lost drives resistance of NSCLC to multiple EGFRi, including erlotinib, gefitinib, afatinib, and osimertinib. SUV420H2 catalyzes trimethylation of histone H4 lysine-20, a modification required for gene repression and maintenance of heterochromatin. Here we show that loss of SUV420H2 leads to upregulation of an oncogenic long non-coding RNA, LINC01510 that promotes transcription of the oncogene MET, a component of a major bypass track involved in EGFRi resistance. Significance:Due to an incomplete understanding of the mechanisms involved in promoting resistance to EGFRi, patients often succumb to their disease. Here we identified a global mediator of EGFRi resistance, SUV420H2 that helps to uncover an additional mechanism involved in resistance driven via a major bypass track involving the protooncogene MET. Supplementary information can be found online at Acknowledgments:The authors gratefully acknowledge the support of multiple core facilities from the Purdue

Identification of microRNAs that promote erlotinib resistance in non-small cell lung cancer

“…3B , values below zero) include tumor suppressive miRNAs such as miR-642b-3p [ 53 ] (ranked 2017 out of 2019 tested miRNAs), miR-1304–3p [ 54 ] (2013/2019), miR-127 that targets BCL6 [ 55 ] (2012/2019), and others. Likewise, in a complementary study we conducted where genetic knockouts were screened for their ability to promote resistance, many of the miRNAs that antagonized resistance in this work were found to drive resistance when knocked out [ 31 ], suggesting that they may sensitize cells to erlotinib. Nonetheless, i) since the cell line used for this screen was already sensitive to erlotinib, ii) because validation studies were not conducted, and iii) because the effect of the miRNA in the absence of erlotinib was not determined (the tumor suppressive effect may be independent of synergizing with erlotinib), the additive or synergistic capacity of these miRNAs cannot be determined.…”

“…Although recent investigations have identified roles for multiple oncogenic and tumor suppressive proteins as mediators of erlotinib resistance in NSCLC [ 31 ], with additional knowledge including the involvement of epigenetic modifiers and microRNAs in nearly all cellular processes, it can be speculated that more mediators are yet to be identified. MicroRNAs (miRNAs) are small non-coding RNAs that generally function by negatively regulating protein-coding transcripts.…”

Clustering of Chromatin Remodeling Enzymes Predicts Prognosis and Clinical Benefit of Therapeutic Strategy in Pancreatic Cancer

“…In cervical cancer cells, cells with low levels of SUV39H1 protein have a higher migratory ability in vitro , and SUV39H1 knockdown in vitro enhances cancer cell migration 37 . Loss of SUV420H2 facilitates upregulation of LINC01510, which promotes the transcription of the oncogene MET and EGFR inhibitor resistance in lung cancer 38 . KDM4A serves as a poor prognostic marker and plays an oncogenic role in oral squamous cell carcinoma and nasopharyngeal cancer 39 , 40 .…”