MT: Oligonucleotides: Therapies and Applications, L1-MET, chimeric transcript, cancer cell death, MET protein knockdown, intragenic-LINE1-derived transcript targeting, Therapeutics. Pharmacology, RM1-950

The expression of intragenic long interspersed nuclear elements 1 (LINE1s) can generate chimeric sequences disrupting host gene transcription. Among these, L1-MET, within mesenchymal epithelial transition (MET) oncogene, is particularly interesting, as its expression has been associated with the acquisition of tumorigenic phenotypes and cancer progression. We investigated the effects of targeting L1-MET in eight cancer cell lines derived from breast, lung, and gastrointestinal cancers, as well as in non-transformed human fibroblasts and lymphocytes, using specifically developed modified antisense oligonucleotides. Inhibition of L1-MET resulted in decreased cell viability, increased apoptosis, and gene expression profile reprogramming in cancer cells, including significant downregulation of MET and epidermal growth factor receptor (EGFR) proteins. These effects were related to the L1-MET/MET expression levels and the type of cellular addiction, with pronounced impacts in cells harboring MET gene amplification and EGFR-activating mutations. They were also detectable, though less pronounced, in cancer cells with steady-state levels of MET and EGFR proteins or addiction to other oncogenes. We demonstrate that targeting L1-MET can knockdown MET and EGFR protein. The restricted expression of L1-MET to cancer cells suggests that its inhibition could be an effective strategy to induce death in oncogene-addicted tumor cells and offers a potential means to overcome the limitations of conventional targeted therapies.