The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax.

IF 0.9 Q4 HEMATOLOGY Hemato Pub Date : 2024-09-01 Epub Date: 2024-08-27 DOI:10.3390/hemato5030024
Alexandria P Eiken, Elizabeth Schmitz, Erin M Drengler, Audrey L Smith, Sydney A Skupa, Kabhilan Mohan, Sandeep Rana, Sarbjit Singh, Jayapal Reddy Mallareddy, Grinu Mathew, Amarnath Natarajan, Dalia El-Gamal
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Abstract

Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells.

Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells.

Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics.

Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

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新型抗癌剂 SpiD3 对伊布替尼或 Venetoclax 耐药的 CLL 细胞具有细胞毒性。
背景:B细胞受体(BCR)信号传导是慢性淋巴细胞白血病(CLL)的核心驱动因素,同时激活促生存通路(如NF-κB)和异常抗凋亡机制(如BCL2),最终导致CLL细胞存活和耐药。伊布替尼(BTK 抑制剂)和 Venetoclax(BCL2 抑制剂)等一线靶向疗法从根本上改善了 CLL 的治疗。然而,持续存在的CLL细胞导致约20%的患者复发,这表明抑制剂耐药的难治性CLL的需求尚未得到满足。SpiD3 是类似物 19 的新型螺环二聚体,具有 NF-κB 抑制活性和临床前抗癌特性。最近,我们发现 SpiD3 可抑制 CLL 细胞增殖,并通过促进未折叠蛋白反应(UPR)途径的无效激活和活性氧(ROS)的生成,抑制 CLL 细胞的蛋白质合成,从而诱导细胞毒性:我们利用对伊布替尼和韦尼替尼耐药的CLL细胞进行了RNA测序,以探索对抑制剂耐药和经SpiD3处理的CLL细胞的潜在弱点:结果:对伊布替尼或venetoclax耐药的CLL细胞系进行的转录组分析表明,铁变态反应、UPR信号转导和氧化应激是受SpiD3处理调节的主要通路。通过研究抑制剂耐药的CLL细胞中SpiD3诱导的蛋白聚集、ROS产生和铁蛋白沉积,我们的研究结果证明了SpiD3治疗对目前一线CLL疗法耐药的细胞株具有细胞毒性:我们的研究结果证明,SpiD3 是治疗复发/难治性 CLL 疾病的新型药物。
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1.30
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审稿时长
11 weeks
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