Predictors of response to venetoclax and therapeutic potential of CDK7 inhibition in multiple myeloma

Blood Neoplasia Pub Date : 2024-10-14 DOI:10.1016/j.bneo.2024.100049

Rudra P. Dutta , Santiago Thibaud , Violetta Leshchenko , Meghana Ram , David T. Melnekoff , Sherry Bhalla , Paula Restrepo , Vikas A. Gupta , Benjamin G. Barwick , Scott Newman , Jonathan McCafferty , Feras Hantash , Ajay K. Nooka , Hearn J. Cho , Shambavi Richard , Cesar Rodriguez , Adriana Rossi , Larysa Sanchez , Ajai Chari , Lawrence H. Boise , Alessandro Laganà

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Abstract

Venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, has emerged as a promising therapeutic agent for multiple myeloma (MM), particularly in patients harboring the t(11;14) translocation. In this study, we set out to identify markers of sensitivity and resistance to venetoclax in a real-world patient population, aiming to facilitate the development of personalized therapeutic strategies. Through the analysis of RNA sequencing (RNA-seq) data from relapsed/refractory patients treated with venetoclax, either as a single agent or in combination with other drugs, we unveiled a novel 6-gene signature that significantly stratified patients into risk groups for relapse and further validated its clinical relevance in 2 independent clinical and ex vivo data sets. Our analysis also highlighted the negative impact of chromosome 1q gain, which harbors the myeloid cell leukemia-1 (MCL1) gene, on progression-free survival, even in t(11;14)-positive patients. Encouraged by the well-documented role of MCL1 in resistance to venetoclax in various malignancies and the prognostic importance of the BCL2/MCL1 ratio in our cohort, we explored Cyclin-Dependent Kinase 7 (CDK7) inhibition as a potential strategy to overcome venetoclax resistance. In vitro experiments demonstrated that CRISPR-Cas9–mediated CDK7 depletion led to decreased MCL1 levels, enhancing the sensitivity of MM cells to venetoclax. Moreover, the combination of the CDK7 inhibitor THZ1 with venetoclax markedly induced cell death in venetoclax-resistant MM cells harboring 1q gain, thus offering a rational therapeutic approach, particularly for patients with this aberration. Overall, these findings provide important insights for optimizing venetoclax-based therapeutic strategies in MM.

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多发性骨髓瘤患者对venetoclax反应的预测因素和CDK7抑制剂的治疗潜力

摘要Venetoclax是一种选择性B细胞淋巴瘤2（BCL2）抑制剂，已成为治疗多发性骨髓瘤（MM）的一种有前途的药物，尤其是对携带t（11;14）易位的患者。在这项研究中，我们试图在现实世界的患者群体中找出对 venetoclax 敏感和耐药的标志物，以促进个性化治疗策略的开发。通过分析复发/难治患者的RNA测序（RNA-seq）数据，我们发现了一个新的6基因特征，它能显著地将患者分为复发风险组，并在2个独立的临床和体内外数据集中进一步验证了其临床相关性。我们的分析还强调了携带髓系细胞白血病-1（MCL1）基因的 1q 染色体增益对无进展生存期的负面影响，即使在 t(11;14)阳性患者中也是如此。在各种恶性肿瘤中，MCL1在文尼他克耐药中的作用已得到充分证实，而且在我们的队列中，BCL2/MCL1比值对预后具有重要意义，受此鼓舞，我们探索了抑制细胞周期蛋白依赖性激酶7（CDK7）作为克服文尼他克耐药的一种潜在策略。体外实验表明，CRISPR-Cas9介导的CDK7去除会导致MCL1水平下降，从而提高MM细胞对venetoclax的敏感性。此外，CDK7抑制剂THZ1与venetoclax联用可明显诱导携带1q增益的venetoclax耐药MM细胞死亡，从而提供了一种合理的治疗方法，尤其适用于有这种畸变的患者。总之，这些发现为优化基于文替可克的MM治疗策略提供了重要启示。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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