Abstract 1836: Induction of secreted soluble decoy EGFR variants by splicing interference overcomes drug resistance in human non-small cell lung cancer
| Autor: | Lee Spraggon, Elisa de Stanchina, Luca Cartegni, Jeong Eun Park |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:1836-1836 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Activation of the epidermal growth factor receptor (EGFR) is involved in the oncogenesis of multiple cancers, particularly lung cancer. Current treatments are limited by the appearance of TKI resistance from secondary somatic mutations in the EGFR gene, such as the T790M mutation (>50% of biopsies) in the EGFR kinase domain following erlotinib or gefitinib treatment. As these tumors are still EGFR-dependent, EGFR remains a prime therapeutic target in NSCLC. We have recently described multiple natural soluble decoy isoforms for multiple RTKs, including EGFR, which depend on the differential inclusion of functional domains by alternative splicing. We employ antisense oligo nucleotide (ASO) to reprogram EGFR pre-mRNA processing in order to increase expression of mRNA variants that encode for dominant-negative, soluble decoys EGFR (sdEGFR), at the expense of the oncogenic full-length EGFR receptor. These alternative splicing isoforms are generated via intronic polyadenylation (IPA) of pre-mRNA in a U1-snRNP (U1)-dependent manner. More specifically, we are able to induce the sdEGFR variants by using specific ASOs, designed to block the upstream U1 binding site and thus activate the appropriate IPA sites. Here, we show that our novel strategy effectively induces the expression of potent natural inhibitors of EGFR signaling in treatment-refractory lung cancer models in vitro and in vivo, leading to suppression of downstream pathways and tumor growth inhibition. The ASO-induced natural sdEGFR compounds function in a dominant-negative manner and induce dramatic cell death in NSCLC cells harboring multiple activating and resistance EGFR mutations, and thus provides a novel alternative strategy for treatment of refractory NSCLC, to overcome resistance mediated by the EGFR secondary mutations (including T790M, C797S and others). Citation Format: Jeong Eun Park, Lee Spraggon, Elisa de Stanchina, Luca Cartegni. Induction of secreted soluble decoy EGFR variants by splicing interference overcomes drug resistance in human non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1836. |
| Databáze: | OpenAIRE |
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