The Anti-Myeloma Efficacy of TAS0612, a Triple Inhibitor of RSK, AKT, and S6K, and Itssynergistic Combination with Venetoclax in Multiple Myeloma Irrespective of Cytogeneticabnormalities

Overcoming the complex inter-patient and intra-clonal heterogeneity of cytogenetic, genetic, and molecular abnormalities has remained the research target for developing a universally active treatment strategy against multiple myeloma (MM).

We have previously identified the essential roles of the PDPK1/RSK2 axis in the pathophysiology of MM, regardless of its cytogenetic, genetic, and molecular profiles. In this scenario, the sustained activation of the N-kinase terminal domain (NTKD) of RSK2 as the result of constitutive active PDPK1 with miR-375 repression plays pivotal roles in myeloma cell proliferation and survival as a downstream signaling output hub of Ras/Raf/ERK pathway (Shimura Y, Mol Cancer Ther 2012; Chinen Y, Cancer Res 2014; Tatekawa S, Br J Haematol 2017). In addition, we have revealed the complementary role of AKT to RSK2 by modulating various critical gene sets involved in myeloma pathophysiology, such as MYC (Isa R, Int J Mol Sci 2022).

Based on these, this study investigated the anti-myeloma efficacy of TAS0612, a triple inhibitor targeting RSK, including RSK2, AKT, and S6K (Taiho Oncology Inc., Princeton, NJ). As the results, TAS0612 showed dose-dependent growth inhibitory effects through the induction of cell cycle blockade and apoptosis in all seven human myeloma-derived cell lines (HMCLs) with diverse cytogenetic, genetic, and molecular profiles examined. In addition, ex vivo treatment with TAS0612 demonstrated robust cell reductive effects in patient-derived primary myeloma cells from 18 patients, including those with newly diagnosed MM (n=7) and with relapsed/refractory MM (n=11), regardless of their patterns of cytogenetic abnormalities. At the molecular level, TAS0612, by its binding, induced the accumulation of p-total RSK^Ser380, p-AKT^Ser473, and p-S6K^Thr389, followed by the subsequent inactivation of their respective target substrates, such as YB1. Comprehensive molecular analysis revealed the concomitant upregulation of several tumor suppressor genes, including TP53INP, HBP1, FBXO32, and YPEL3, along with the downregulation of gene sets involved in Myc and mTOR pathways. Intriguingly, analysis using RNA expression and survival data from the MMRF CoMMpass Study indicated that TAS0612 treatment modulated the expression of a series of prognosis-relevant genes in myeloma cells. Of note, TAS0612 upregulated a series of genes significantly associated with favorable prognosis, while it simultaneously downregulated various genes significantly associated with poor prognosis in the MMRF CoMMpass Study.

Next, during the search for a strategy that can enhance the anti-myeloma efficacy of TAS0612, we identified the combinatory use of venetoclax (VEN), a BCL2 selective BH3-mimetic, as the promising partner agent with TAS0612. Although VEN has been shown to be most selectively active on myeloma cells with t(11;14) chromosomal translocation, our study revealed the additive to synergistic apoptosis-inducing effects of TAS0612 and VEN in all six HMCLs examined, irrespective of the presence or absence of t(11;14). Thus, the combinatory use of TAS0612 may overcome the weak point of VEN, and enables the broader use in MM. Indeed, the addition of marginally lethal concentrations of VEN, which increased apoptotic cells by 1.3-fold (range 1.1-1.5) compared to untreated cells, to TAS0612, which increased apoptotic cells by 5.3-fold (range 1.2-17.7), resulted in an 11.0-fold (range 4.9-21.7) increase in apoptotic cells in the six HMCLs examined. Further investigation suggested that the upregulation of NOXA and BIM by TAS0612 may underly the combinatory anti-myeloma effects with VEN. Finally, TAS0612 treatment showed the dose-dependent anti-myeloma effect in an in vivo myeloma model xenografted with HMCL, and this in vivo anti-myeloma effect of TAS0612 was significantly enhanced by the combinatory use of VEN, even against HMCLs not harboring t(11;14).

These suggest that TAS0612, as the single agent, is an attractive candidate drug for MM regardless of cytogenetic and genetic abnormalities. Moreover, combining TAS0612 with VEN represents a potent new therapeutic strategy for MM, irrespective of the presence of t(11;14), facilitating its future clinical development.