Wednesday, December 4, 2024
12/4/2024
Velcrin compounds kill cancer cells expressing elevated levels of PDE3A and SLFN12 by inducing complex formation between these two proteins. Velcrin-induced PDE3A-SLFN12 complexes are heterodimers comprised of two PDE3A proteins and two SLFN12 proteins. We hypothesize that the sole function of complex formation in velcrin response is to dimerize SLFN12, and that SLFN12 dimers are the active form of the SLFN12 RNase, resulting in cytotoxicity mediated by degradation of the SLFN12 substrate, tRNA-Leu-TAA. We will test this hypothesis with the experiments outlined in this proposal. First, we will determine whether expression of high concentrations of SLFN12 can induce tRNA-Leu-TAA degradation and cytotoxicity in the absence of PDE3A. Second, we will take a loss-of-function approach and determine whether a point mutation at the SLFN12 homodimer interface, I131Q, can inhibit SLFN12-mediated cytotoxicity with or without velcrin treatment. Third, we will take a gain-of-function approach and assess whether FKBP-mediated chemically-induced homodimerization of SLFN12 results in tRNA-Leu-TAA degradation and cytotoxicity in the absence of PDE3A or velcrin treatment. The ultimate goal of this research is to determine whether SLFN12 dimerization can be leveraged to create an entirely new cancer therapeutic modality. If we find that dimerization of SLFN12 is necessary and sufficient for RNase activation, we envision developing a new type of small molecule that will tether SLFN12 to cancer-specific dimers, such as RAF dimers in RAS-mutant cells, mimicking the role of PDE3A in the velcrin-mediated cytotoxic response.
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