Abstract 1726: Targeted epigenomic control of MYC as a strategy to treat EGFR inhibitor-resistant NSCLC

Abstract EGFR tyrosine kinase inhibitors (EGFRi) have improved outcomes for non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. However, patients receiving EGFRi therapy frequently relapse with an EGFR T790M mutation. While osimertinib, a third generation EGFRi, blocks EGFR T790M activity, resistance eventually develops through various EGFR-dependent and EGFR-independent mechanisms, such as acquiring additional mutations in EGFR (e. g. C797S), activating bypass signaling pathways, or undergoing an epithelial to mesenchymal transition (EMT). MYC is a master transcription factor critical for mediating oncogenic signal transduction and has been implicated in EGFRi resistance, suggesting that MYC targeting may overcome multiple EGFRi resistance mechanisms. To evaluate this, we have developed a NSCLC-specific programmable epigenomic mRNA therapy, termed a MYC epigenomic controller (NSCLC MYC-EC), designed to selectively target regulatory elements in MYC’s insulated genomic domain and downregulate MYC expression. We have previously shown that NSCLC MYC-EC effectively decreases MYC expression pre-transcriptionally and have demonstrated that MYC-EC combination with osimertinib synergistically reduces viability of EGFR mutant NSCLC cells. Here, we demonstrate NSCLC MYC-EC activity in models that have developed EGFRi resistance through EGFR-dependent and -independent mechanisms. To test the effect of NSCLC MYC-EC in NSCLC cells with T790M mutant EGFR, we treated H1975 (L858R, T790M) and PC9-T790M cells (del19, engineered T790M) with MYC-EC alone or in combination with osimertinib. MYC-EC combination with osimertinib enhanced MYC protein downregulation and synergistically reduced cell viability in both models. To evaluate the effect of MYC-EC in osimertinib-resistant cells, we engineered H1975 and PC9-T790M cells with an EGFR C797S mutation. While osimertinib treatment did not impact cell viability in these models, MYC-EC maintained activity, downregulating MYC levels and reducing cell viability. To investigate MYC-EC activity in cells with alternative resistance mechanisms, we generated osimertinib-resistant H1975 cells by stepwise dose escalation. Protein analysis showed highly reduced phospho-EGFR levels, suggesting an EGFR-independent mechanism of survival. RNA-sequencing analysis revealed that EMT pathway was highly activated in these resistant cells. Importantly, this model retained sensitivity to NSCLC MYC-EC treatment, demonstrating that selectively targeting MYC can treat osimertinib-resistant NSCLC cells with a mesenchymal phenotype. Together, these data demonstrate that pre-transcriptional downregulation of MYC through NSCLC MYC-EC treatment effectively inhibits viability of EGFRi-resistant NSCLC through both EGFR-dependent and -independent mechanisms and supports the development of NSCLC MYC-EC in EGFRi-resistant NSCLC. Citation Format: Eugine Lee, Padraich Flahardy, Cameron Vergato, Stephen Siecinski, Justin Chen, Charles O’Donnell, Graeme Hodgson, Defne Yarar, Thomas McCauley. Targeted epigenomic control of MYC as a strategy to treat EGFR inhibitor-resistant NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1726.