Abstract 2006: Deciphering the interplay of β-catenin/YAP signaling and alveolar lineage plasticity during targeted therapy in non-small cell lung cancer

Abstract Molecularly targeted therapies have significantly enhanced clinical outcomes by directly addressing oncogenic driver mutations in genes such as EGFR. However, despite the success of treatments targeting these mutations, long-term patient survival remains limited. This study investigates the molecular mechanisms underlying drug-tolerance in response to targeted therapies in non-small cell lung cancer (NSCLC). Using single-cell RNA sequencing of oncogene-driven human NSCLCs at the residual disease (RD) state during active targeted therapy, our investigation reveals an increase of an alveolar type I/II (AT1/2) mixed lineage program in surviving cancer cells, resembling an alveolar cell-like state. We observed increased WNT3A/4 ligands, FZD2 receptors, β-catenin signaling, and AT1/2 signatures at the RD stage. Consistent with clinical results, AT1/2 signatures and target genes of β-catenin and YAP are increased in drug-tolerant persister (DTP) cells in preclinical models. Additionally, we discovered that β-catenin and YAP form a stable nuclear protein complex in DTP cells. Disrupting β-catenin/YAP protein expression and stability in DTP cells by knocking down FZD2 or interrupting the destruction complex of β-catenin/YAP leads to re-sensitization to the EGFR inhibitor Osimertinib, suggesting a potential therapeutic approach. Furthermore, this therapeutic strategy decreased AT1/2 gene signatures. Our results highlight an interdependence between β-catenin and YAP, with both proteins playing crucial roles in sustaining DTP cells and promoting the alveolar cell like lineage plasticity. These findings shed light on the complex interplay between β-catenin/YAP signaling and alveolar signatures in the residual cancer state, offering mechanistic insights and potential therapeutic strategies to address drug tolerance and improve clinical outcomes. Citation Format: Yu-Ting Chou, Wei Wu, Daniel Kerr, Macey Slota, Trever Bivona. Deciphering the interplay of β-catenin/YAP signaling and alveolar lineage plasticity during targeted therapy in non-small cell lung cancer [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(6_Suppl):Abstract nr 2006.