Inhibition of FOXM1 Synergizes with BH3 Mimetics Venetoclax and Sonrotoclax in Killing Multiple Myeloma Cells through Repressing MYC Pathway

Abstract Relapsed and refractory multiple myeloma (RRMM) remains the leading cause of MM mortality. FOXM1 is strongly associated with RRMM, making it a compelling therapeutic target. Through three low‐throughput screenings, we have identified nine FDA‐approved drugs, including the BH3 mimetic Venetoclax, that synergize with FOXM1 inhibitor NB73 in killing MM cells. Venetoclax has shown effects in 6% of non‐t(11;14) and 27% of t(11;14) MM cases. The NB73‐Venetoclax combination barely induces acute toxicity in vivo and represses MM cells in vivo and ex vivo. NB73 enhances the ubiquitination and proteasomal degradation of FOXM1, an effect further amplified by Venetoclax. The NB73‐Venetoclax combination abolishes FOXM1's binding to promoters of key MYC pathway genes, such as PLK1, leading to significant downregulation of their expression. Furthermore, the PLK1‐specific inhibitor GSK461364 synergizes with NB73 to inhibit MM cell growth. Interestingly, NB73 does not sensitize U266 cells, a Venetoclax‐resistant t(11;14) MM cell line expressing high FOXM1, to Venetoclax treatment, which is corrected by a new‐generation BH3 mimetic Sonrotoclax and ALK inhibitor Ceritinib. Collectively, targeting FOXM1 demonstrates significant potential for enhancing the efficacy of FDA‐approved drugs in RRMM. These findings shed new light on the discouraging outcomes of the Phase‐III CANOVA study centering Venetoclax with an encouraging molecular clue.