Abstract 3304: Modulation of enhancer accessibility by SMARCA2 PROTACs synergize with TEAD inhibitors to suppress growth of SMARCA4 mutant lung cancers
Authors: Kotagiri Sasi , Blazanin Nicholas , Qudrattulah Mohammad , Xi Yuanxin , Wang Jing , Lissanu Yonathan 
Published: March 2024

Abstract
The SWI/SNF chromatin remodeling complex is frequently mutated in non-small cell lung cancer with a frequency of 33% in advanced stage disease, making it the most commonly altered complex in lung cancer. Among the various subunits of the SWI/SNF complex, SMARCA4 and ARID1A are by far the most frequently mutated. Importantly, multiple clinical reports have shown that SMARCA4 mutant lung cancers have one of the worst prognosis among genetically defined lung cancer subtypes and lack response to both immunotherapy and KRAS G12C inhibitors. Recent reports, and our own data, have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 could be a high value therapeutic target. Unfortunately, the discovery of selective inhibitors of SMARCA2 has so far been challenging. To overcome this hurdle, we have recently developed novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induced degradation of SMARCA2. Importantly, we showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells. Mechanistically, we demonstrated that YD23 decreased chromatin accessibility only in SMARCA4 deficient cells. In particular, SMARCA2 degradation profoundly decreased chromatin accessibility at enhancers of a number of genes with cell cycle and cell growth regulatory roles. Gene expression profiling and pathway analysis indicated that cell cycle genes were downregulated by YD23 consistent with the reduced chromatin accessibility at their cis-regulatory regions. We further showed that YD23 robustly inhibited growth of SMARCA4-mutant xenograft tumors. While this is promising, SMARCA2 degradation by itself does not induce regression of tumors highlighting the need for identification of efficacious combination strategies. Using integrative gene expression, ATAC-Seq and CUT&RUN assays, we uncover a critical role for YAP/TEAD transcription factor signaling axis in mediating pro-growth phenotypes in SMARCA4 mutant tumors. Finally, we show that the combination of TEAD inhibitors synergizes with YD23 to induce profound tumor growth inhibition. In conclusion, our study provides a mechanistic basis for the anti-tumor action of SMARCA2 degraders and introduces a novel combination strategy for future clinical development against a genetically defined subtype of lung cancer with dismal prognosis.
Citation Format: Sasi Kotagiri, Nicholas Blazanin, Mohammad Qudrattulah, Yuanxin Xi, Jing Wang, Yonathan Lissanu. Modulation of enhancer accessibility by SMARCA2 PROTACs synergize with TEAD inhibitors to suppress growth of SMARCA4 mutant lung cancers [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 3304.