Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention

IF 12.9 1区 医学 Q1 HEMATOLOGY
Rodrigo Fonseca, Yuan Xiao Zhu, Laura A. Bruins, Joseph Ahmann, Cecilia de Bonolo Campos, Esteban Braggio, Xianfeng Chen, Mariano Arribas, Susie Darvish, Seth Welsh, Erin Meermeier, Kiran K. Mangalaparthi, Richard K. Kandasamy, Greg Ahmann, J. Erin Wiedmeier-Nutor, Akhilesh Pandey, Marta Chesi, P. Leif Bergsagel, Rafael Fonseca
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Abstract

Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members. Notably, the re-introduction of BIM into resistant cells restored VTX sensitivity and synergized with MCL-1 inhibitors. Upstream signaling pathways, including growth factor receptor tyrosine kinase (RTK) and phosphoinositide-3-kinase (PI3K) were implicated in this dysregulation. Simultaneous inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Post-translational modifications of MCL-1, particularly its stabilization via acetylation and phosphorylation, were investigated, although their inhibition only marginally increased VTX sensitivity. Lastly, the inhibition of AURKA and mitochondrial respiration also improved VTX sensitivity in some resistant HMCLs. Our findings suggest that combining VTX with MCL-1 and BCL-XL inhibitors or PIK3/RTK inhibitors holds potential for overcoming resistance. The study illustrates the importance of understanding molecular determinants of resistance to develop tailored therapeutic strategies.

Abstract Image

探讨BCL2在多发性骨髓瘤venetoclax耐药中的调控和上游信号转导:治疗干预的潜在途径
研究venetoclax (VTX)在多发性骨髓瘤(MM)中的耐药性对于开发新的治疗策略来解决耐药性至关重要。我们对已建立的vtx耐药等基因人类骨髓瘤细胞系(HMCL)和原发MM患者样本在vtx治疗前后进行了多组学表征。转录组学和蛋白质组学分析显示,耐药主要与BCL-2家族蛋白失调有关,包括抗凋亡蛋白如MCL-1、BCL-XL、BCL-2的上调,以及促凋亡成员的下调。值得注意的是,将BIM重新引入耐药细胞恢复了VTX的敏感性,并与MCL-1抑制剂协同作用。上游信号通路,包括生长因子受体酪氨酸激酶(RTK)和磷酸肌醇-3激酶(PI3K)参与了这种失调。同时抑制MCL-1、BCL-XL和上游PI3K、RTK (FGF、EGF和IGF1)介导的信号传导增强了VTX的敏感性。MCL-1的翻译后修饰,特别是其通过乙酰化和磷酸化的稳定性,被研究,尽管它们的抑制只略微增加了VTX的敏感性。最后,AURKA和线粒体呼吸的抑制也改善了一些耐药hmcs的VTX敏感性。我们的研究结果表明,VTX与MCL-1和BCL-XL抑制剂或PIK3/RTK抑制剂联合使用具有克服耐药性的潜力。这项研究说明了了解耐药性的分子决定因素对于制定量身定制的治疗策略的重要性。
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来源期刊
CiteScore
16.70
自引率
2.30%
发文量
153
审稿时长
>12 weeks
期刊介绍: Blood Cancer Journal is dedicated to publishing high-quality articles related to hematologic malignancies and related disorders. The journal welcomes submissions of original research, reviews, guidelines, and letters that are deemed to have a significant impact in the field. While the journal covers a wide range of topics, it particularly focuses on areas such as: Preclinical studies of new compounds, especially those that provide mechanistic insights Clinical trials and observations Reviews related to new drugs and current management of hematologic malignancies Novel observations related to new mutations, molecular pathways, and tumor genomics Blood Cancer Journal offers a forum for expedited publication of novel observations regarding new mutations or altered pathways.
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