Targeting RNA Splicing Overcomes Leukemia Resistance to BCL2 Inhibition

Despite the recent approvals of several targeted therapies for acute myeloid leukemia (AML), patient relapse following long-term drug exposure remains a clinical challenge, highlighting the need to identify combinatorial treatment regimens that overcome therapeutic resistance. To study candidate genes that underlie resistance to AML therapies, Wang, Pineda, Kim, and colleagues performed a genome-wide CRISPR–Cas9 knockout screen in a human AML cell line treated with a panel of clinically approved AML drugs, including venetoclax, an inhibitor of the antiapoptotic protein BCL2, and showed that many guides that targeted genes encoding for RNA splicing factors specifically sensitized AML cells to venetoclax. These findings were further supported by a subsequent CRISPR screen focused on RNA binding proteins, in which inactivation of RBM10, which encodes an RNA splicing regulator, emerged as a top candidate for conferring sensitivity to venetoclax. When immunodeficient mice were injected with control or RBM10-knockout human AML cells prior to treatment with vehicle or venetoclax, RBM10 knockout led to reduced tumor burden and prolonged survival in the context of venetoclax. Profiling of RBM10–RNA interactions, in conjunction with RNA sequencing analysis of RBM10-knockout cells, suggested that RBM10 broadly regulates exon usage and that RBM10 knockout sensitizes cells to venetoclax in part by promoting the missplicing of XIAP, a gene that encodes an inhibitor of apoptosis. Beyond RBM10, other genes that scored as sensitizers to venetoclax in the initial CRISPR screens included multiple splicing factors dependent on posttranslational modifications via the kinases CLK and DYRK, motivating the development of SM09419, a pan-CLK/DYRK small-molecule inhibitor. SM09419 synergized with venetoclax in vitro and overcame venetoclax resistance in vivo by reducing RNA splicing efficiency and facilitating the missplicing and downregulation of not only XIAP but also the prosurvival gene MCL1 and the receptor tyrosine kinase FLT3. In summary, these findings highlight the dependence of AML on RNA splicing machinery and propose the clinical potential of multiple therapeutic strategies to overcome venetoclax resistance.

Wang E, Pineda JMB, Kim WJ, Chen S, Bourcier J, Stahl M, et al. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia. Cancer Cell 2022 Dec 22 [Epub ahead of print].

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