Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma

Abstract

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 (IC50) and hence sensitivity/resistance to venetoclax, bortezomib and S63845 were determined. Key findings Venetoclax (IC50 ≥100 nm), bortezomib (IC50 ≥50 nm) and S63845 (IC50 ≥100 nm) resistance was observed in nine (75%), three (25%) and six (50%) HMCLs, respectively. Moreover, venetoclax sensitivity was independent of bortezomib (R2 = 0.1107) or S63845 (R2 = 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.