Characterization of Asciminib-Resistant Philadelphia Chromosome-Positive Cells.

Background: Asciminib is approved for treating patients with chronic-phase chronic myeloid leukemia who were previously treated with two or more tyrosine kinase inhibitors or those with T315I mutation. However, the mechanisms underlying asciminib resistance remain unclear. Methods: In this study, we established a new asciminib-resistant cell line. We examined BCR::ABL1 gene mutation analysis and the effects of conventional chronic myelogenous leukemia inhibitors. Results: Direct sequencing revealed Y139D and T315I mutations in asciminib-resistant cells. Ponatinib and omacetaxine were effective against asciminib-resistant cells. Conclusions: Y139D and T315I mutations are extremely resistant to asciminib. Ponatinib and omacetaxine show potential for treating asciminib-resistant chronic myeloid leukemia.

Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells.

The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). However, resistance to ABL TKIs can develop in CML patients due to BCR::ABL1 point mutations and CML leukemia stem cell (LSC). Aurora kinases are essential kinases for cell division and regulate mitosis, especially the process of chromosomal segregation. Aurora kinase members also promote cancer cell survival and proliferation. This study analyzed whether aurora kinases were regulated in the progression of CML. It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. The expressions of AURKA and AURKB were higher in the CML cells compared with normal cells using a public database (GSE100026). Asciminib or LY3295668 alone inhibited CML cells after 72 h, and cellular cytotoxicity was increased. The combined use of Asciminib and LY3295668 increased superior efficacy compared with either drug alone. Colony formation was reduced by cotreatment with asciminib and LY3295668. In the cell-cycle analyses, LY3295668 induced G2/M arrest. Cell populations in the sub-G1 phase were observed when cotreating with asciminib and LY3295668. The combination treatment also changed the mitochondrial membrane potential. In addition, AURKA shRNA transfectant cells had increased asciminib sensitivity. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.

Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects.

Aim: This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma (MM) despite significant therapeutic advances and the introduction of novel agents. Our study focused on how myeloma cells mediate the metabolic pathways essential for survival. Therefore, we examined the role of glutaminolysis in this process. Methods: We investigated the role of glutaminolysis in myeloma cell growth. In addition, we analyzed the ability of CB-839 (telaglenastat), a glutaminase (GLS) inhibitor, to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase (HDAC) inhibitors. Results: Glutamate deprivation significantly reduced MM cell proliferation. We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls. CB-839 inhibits MM cell proliferation in a dose-dependent manner, resulting in enhanced cytotoxicity. Additionally, intracellular α-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration. Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity. Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results. Compared to control cells, these cells also showed increased sensitivity to panobinostat. Conclusion: Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.