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Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells

[Image: see text] 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 AT...

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Autores principales: Priya, Bhanu, Dubey, Gurudutt, Kirubakaran, Sivapriya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909806/
https://www.ncbi.nlm.nih.gov/pubmed/36777575
http://dx.doi.org/10.1021/acsomega.2c07356
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author Priya, Bhanu
Dubey, Gurudutt
Kirubakaran, Sivapriya
author_facet Priya, Bhanu
Dubey, Gurudutt
Kirubakaran, Sivapriya
author_sort Priya, Bhanu
collection PubMed
description [Image: see text] 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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spelling pubmed-99098062023-02-10 Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells Priya, Bhanu Dubey, Gurudutt Kirubakaran, Sivapriya ACS Omega [Image: see text] 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. American Chemical Society 2023-01-30 /pmc/articles/PMC9909806/ /pubmed/36777575 http://dx.doi.org/10.1021/acsomega.2c07356 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Priya, Bhanu
Dubey, Gurudutt
Kirubakaran, Sivapriya
Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
title Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
title_full Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
title_fullStr Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
title_full_unstemmed Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
title_short Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells
title_sort exploring spk98 for the selective sensitization of atm- or p53-deficient cancer cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909806/
https://www.ncbi.nlm.nih.gov/pubmed/36777575
http://dx.doi.org/10.1021/acsomega.2c07356
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