AI Article Synopsis
- Venetoclax, a BCL2 inhibitor, shows potential anti-tumor activity in myeloma, particularly in patients with t(11;14), but its effectiveness can vary based on resistance in some human myeloma cell lines (HMCLs).
- The study assessed venetoclax sensitivity alongside other drugs, finding that 75% of HMCLs were resistant to it and emphasizing a correlation between venetoclax sensitivity and specific gene expression ratios.
- Combining venetoclax with S63845, a novel MCL1 inhibitor, not only enhances sensitivity compared to bortezomib but also restores sensitivity in previously resistant HMCLs, suggesting a promising direction for future clinical trials in myel
Article Abstract
Objectives: Venetoclax, an orally available BCL2-selective inhibitor, has demonstrated promising single-agent anti-tumour activity in myeloma especially patients with t(11;14). Herein, whether venetoclax sensitivity could be enhanced or restored in combination with bortezomib or S63845, a novel MCL1-selective inhibitor, was examined in human myeloma cell lines (HMCLs), including bortezomib-resistant HMCLs.
Methods: By MTS assay, half-maximal inhibitory concentration (IC ) and hence sensitivity/resistance to venetoclax, bortezomib and S63845 were determined.
Key Findings: Venetoclax (IC ≥100 nm), bortezomib (IC ≥50 nm) and S63845 (IC ≥100 nm) resistance was observed in nine (75%), three (25%) and six (50%) HMCLs, respectively. Moreover, venetoclax sensitivity was independent of bortezomib (R = 0.1107) or S63845 (R = 0.0213) sensitivity. Venetoclax sensitivity correlated with high mRNA ratio of BCL2/MCL1 (P = 0.0091), BCL2/BCL2L1 (P = 0.0182) and low MCL1 expression (P = 0.0091). In HMCLs sensitive to both venetoclax and bortezomib/S63845, venetoclax combined with S63845 showed stronger synergistic effect than combined with bortezomib. Moreover, in venetoclax-resistant HMCLs, S63845, but not bortezomib, significantly restored venetoclax sensitivity. Conversely, bortezomib combined with S63845 did not result in augmented bortezomib sensitivity or abolishment of bortezomib resistance.
Conclusions: Regardless of t(11;14), combination of venetoclax with S63845 is a promising strategy in enhancing venetoclax sensitivity or overcoming venetoclax resistance in myeloma therapy, hence warrant future clinical studies.
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