Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas

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ABSTRACT Among aggressive lymphomas, the Diffuse large B-cell lymphomas (DLBCLs) are among the most highly proliferative, and have massive requirements for production of metabolic precursors. Along these lines we recently identified NAD+ dependent lysine deacetylase SIRT3, as a master regulator of mitochondrial stress metabolism, as a critical driver of DLBCL growth and survival. We showed that SIRT3 loss of function in DLBCL cells kills lymphomas by disrupting their ability to use glutamine and other amino acids in the TCA cycle, which triggers destructive autophagy – both in vitro and in vivo. Importantly, we created the mitochondrial targeted SIRT3 selective small molecule YC8-02 that precisely mimics the effect of SIRT3 depletion and potently killed DLBCL cells in vitro and in vivo. These compounds yielded further enhanced killing effects in combination with targeted therapies such as venetoclax as well with chemotherapy drugs commonly used to treat DLBCLs. Finally, our mechanistic data point to pathways in cells that could eventually lead to resistance to SIRT3 targeted therapy, as well as ways to prevent this from happening so as to yield maximal therapeutic efficacy. An overarching challenge in delivering precision medicine for DLBCL patients is their marked genetic heterogeneity and extreme abundance of somatic mutations. There are currently no targeted agents with activity and targets relevant to more than a small fraction of patients. However, we identified SIRT3 as a broadly relevant and critical non-oncogene addiction that is required by DLBCLs independent of their genetic background. Through this proposal we provide the basis for i) translating SIRT3 inhibitors to the clinic, ii) understanding and mitigating potential resistance mechanisms, and iii) incorporating SIRT3 inhibitors into rationally designed anti-lymphoma regimens with broad relevance for the subsets of patients who desperately need improved therapies. Our proposal uses state of the art model systems physiologically relevant to these complex tumors, and is poised to deliver highly impactful outcomes from the scientific and clinical perspective.