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  • Title: Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells.
    Author: Priya B, Dubey G, Kirubakaran S.
    Journal: ACS Omega; 2023 Feb 07; 8(5):4954-4962. PubMed ID: 36777575.
    Abstract:
    Frequent mutation in the ATM/P53 signaling pathway has been documented in many human cancers. Reportedly, cancer cells with deficient P53/ATM pathways depend on functional Ataxia-telangiectasia and Rad3-related (ATR) protein for survival. This has prompted research in developing ATR inhibitors for the selective sensitization of cancer cells that are P53/ATM-deficient, but no clinical success has been attained thus far. This study explores the therapeutic potential of SPK98, an analogue of Torin2 in P53- and ATM-deficient cancer cells. Furthermore, the prospect of improving the therapeutic outcome of the genotoxic agent was also explored. SPK98 was shown to inhibit full-length human ATR protein purified from HEK293T cells. Cellular investigation using SPK98 demonstrated that it selectively sensitizes P53- and ATM-deficient cells at low concentrations compared to P53-/ATM-proficient cells. Furthermore, SPK98 drives the cancer cells toward cell death by promoting the formation of DNA double-strand breaks. Taken together, our findings suggest that SPK98 is a promising therapeutic molecule for P53- or ATM-deficient malignancy that merits additional preclinical investigation.
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