https://orcid.org/0000-0001-9794-0151
KEY POINTS
RNA-seq analysis reveals a six-gene signature that stratifies multiple myeloma patients by their predicted response to venetoclax.
This study proposes a novel approach to overcoming this resistance through Cyclin-Dependent Kinase 7 (CDK7) inhibition.
ABSTRACT
Venetoclax, a selective 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-seq data from relapsed/refractory patients treated with venetoclax, either as a single agent or in combination with other drugs, we unveiled a novel six-gene signature that significantly stratified patients into risk groups for relapse and further validated its clinical relevance in two independent clinical and ex vivo datasets. Our analysis also highlighted the negative impact of chromosome 1q gain, which harbors the MCL1 gene, on progression-free survival (PFS), 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.
