Abstract 5364: Multi-omic analyses reveal epigenetic and transcriptomic reprogramming behind ibrutinib-venetoclax resistance development in mantle cell lymphoma

Abstract Mantle cell lymphoma (MCL) is a rare and aggressive form of B-cell lymphoma that is characterized by aberrations in B-cell receptor signaling and BCL-2-mediated apoptotic pathways. MCLs treated with inhibitors of either have shown remarkable response rates but ultimately develop drug resistance, with patients suffering from rapid disease progression and experiencing poor clinical outcomes. Preclinical and clinical studies into the Bruton’s tyrosine kinase inhibitor ibrutinib and the BCL-2 inhibitor ABT-199 (venetoclax) revealed that they were synergistic when combined against MCL and showed significant clinical efficacy, respectively. However, through an unclear mechanism, many cases of MCL similarly developed resistance to combination therapy. To elucidate the mechanisms by which MCL develops drug resistance, we induced resistance to BTKi-venetoclax in 2 patient-derived MCL cell lines, Mino and Rec1, and characterized transcriptional and epigenetic changes using bulk and single-cell RNA and ATAC-seq datasets. We conducted differential expression and accessibility analysis between BTKi-venetoclax-sensitive and resistant samples and identified significantly enriched pathways to find molecular processes that differentiate the two. We show that resistant MCL displays changes at the chromatin and RNA level associated with BCL-2 inhibition, including downregulation of E2F and E2F targets such as cyclin D1. However, we observe that both MCL lines that developed resistance to BTKi-venetoclax upregulate BCL-XL to evade BCL-2 inhibition-mediated apoptosis, likely through activation of the alternative JAK/STAT, interferon, NFKB, and Myc pathways, which are also significantly upregulated. These drastic transcriptomic changes provide an explanation of how resistant MCLs bypass both BCL-2 and BCR-signaling inhibition, leading to survival and neoplastic expansion. Additionally, we identify upregulated genes on both a transcriptional and epigenetic level that encode surface proteins that may inform future targeted therapies. These findings provide mechanistic insights into the transcriptomic reprogramming undertaken by mantle cell lymphoma when developing resistance to BTKi-venetoclax and identify potential vulnerabilities conferred by dual-therapy resistance. They suggest that future therapies optimized against MCL require a combination of immunotherapy and targeted therapies designed to counteract transcriptome reprogramming seen during drug resistance. Citation Format: Kevin Qiu, Jing Gao, Qing Yin, Allen Hu, Zhenjia Wang, Loryn Blackburn, Bijal Shah, Jeffrey W. Craig, Craig Portell, Michael E. Williams, Chongzhi Zang, Jianguo Tao. Multi-omic analyses reveal epigenetic and transcriptomic reprogramming behind ibrutinib-venetoclax resistance development in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5364.