A marker that predicts Venetoclax (ABT-199) sensitivity that can also be targeted with a drug to help multiple myeloma patients.
- Marker that predicts if venetoclax will be an effective treatment in multiple myeloma patients.
- A drug that targets venetoclax resistant multiple myeloma cells to improve treatment in patients.
Multiple myeloma (MM) is a plasma cell malignancy estimated to account for 12K deaths and 32Knew diagnoses in the US in 2021. Despite the use of next-generation drug therapies, MM patients relapse and develop therapy resistance. Approximately 20% of patients succumb to this disease within a short period of time. Resistance is primarily associated with MM cells avoiding cell death (apoptosis) and the inability to reach a threshold needed for these cells to elicit apoptosis. Venetoclax targets a protein called BCL-2, to help cells undergo the process of cell death, allowing cancer cells to self-destruct. It is clinically approved and highly effective in chronic lymphocytic leukemia. However, in multiple myeloma, venetoclax is only effective as a single agent in approximately 6% of MM, underscoring the need to identify biomarkers of patients who will benefit from this potent therapy. Venetoclax is currently being tested in combination therapy in phase I-II trials for MM. Thus, there is also a need to find combination strategies to increase sensitivity to venetoclax. Identifying the right patients and finding better combination regimens with venetoclax can prevent the development of relapse refractory disease.
Emory researchers have discovered a marker to predict resistance to venetoclax in MM patients and treatment to overcome this resistance. Researchers found that MM cell lines that are sensitive to venetoclax exhibited lower activity of the enzyme Succinate Ubiquinone Reductase (SQR), which is involved in the electron transport chain for cell respiration. By inhibiting succinate dehydrogenase (SDH) a mitochondrial enzyme with the inhibitor thenoyltrifluoroacetone (TTFA), MM cells that are resistant to venetoclax exhibit sensitivity to this treatment. Mechanistically inhibition of SDH with venetoclax alters expression and binding properties of the BCL-2 family of proteins bringing a cell closer to the death threshold. Thus, researchers discovered co-treatment of TTFA and venetoclax induces apoptosis in venetoclax resistant myeloma patient cells while healthy cell populations are not affected. These results show SQR activity can be used as a predictive marker of venetoclax sensitivity in MM and known SDH inhibitors can potentially be considered as therapeutics to overcome venetoclax resistance.
In vitro and ex vivo studies testing SQR inhibitors.
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