Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

IF 48.8 1区 医学 Q1 CELL BIOLOGY
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Abstract

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

Abstract Image

在 POU2F-POU2AF 转录因子驱动的恶性肿瘤中瞄准 mSWI/SNF 复合物
POU2F3-POU2AF2/3转录因子复合物是丛细胞系和丛细胞样小细胞肺癌(SCLC)的主调节因子。在这里,我们发现了POU2F3分子亚型SCLC(SCLC-P)对哺乳动物开关/蔗糖不发酵(mSWI/SNF)染色质重塑复合物活性的特殊依赖性。用蛋白水解靶向嵌合体(PROTAC)mSWI/SNF ATPases降解器处理SCLC-P细胞,可将POU2F3及其辅助激活因子从染色质中驱逐出去,并减弱下游信号传导。依赖于 POU2F1/2 辅因子 POU2AF1 的 B 细胞恶性肿瘤对 mSWI/SNF ATPase 降解剂也很敏感,治疗会导致 POU2AF1 和 IRF4 的染色质被逐出,并减少多发性骨髓瘤细胞中的 IRF4 信号传导。在SCLC-P和多发性骨髓瘤的临床前模型中,口服生物可利用的mSWI/SNF ATPase降解剂能显著抑制肿瘤生长,且无毒性迹象。这项研究表明,POU2F-POU2AF驱动的恶性肿瘤对mSWI/SNF复合物有内在依赖性,这是一种治疗脆弱性。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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