Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to chemotherapy by abrogating the ToPBP1/ATR-mediated DNA damage response

Li Ding, Vijay S. Madamsetty, Spencer Kiers, Olga Alekhina, Andrey Ugolkov, John Dube, Yu Zhang, Jin San Zhang, Enfeng Wang, Shamit K. Dutta, Daniel M. Schmitt, Francis J. Giles, Alan P. Kozikowski, Andrew P. Mazar, Debabrata Mukhopadhyay, Daniel D. Billadeau

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a predominantly fatal common malignancy with inadequate treatment options. Glycogen synthase kinase 3b (GSK-3b) is an emerging target in human malignancies including PDAC. Experimental Design: Pancreatic cancer cell lines and patient-derived xenografts were treated with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. Activation of the DNA damage response pathway and S-phase arrest induced by gemcitabine were assessed in pancreatic tumor cells with pharmacologic inhibition or siRNA depletion of GSK-3 kinases by immunoblotting, flow cytometry, and immunofluorescence. Results: 9-ING-41 treatment significantly increased pancreatic tumor cell killing when combined with chemotherapy. Inhibition of GSK-3 by 9-ING-41 prevented gemcitabine-induced S-phase arrest suggesting an impact on the ATR-mediated DNA damage response. Both 9-ING-41 and siRNA depletion of GSK-3 kinases impaired the activation of ATR leading to the phosphorylation and activation of Chk1. Mechanistically, depletion or knockdown of GSK-3 kinases resulted in the degradation of the ATR-interacting protein TopBP1, thus limiting the activation of ATR in response to single-strand DNA damage. Conclusions: These data identify a previously unknown role for GSK-3 kinases in the regulation of the TopBP1/ATR/Chk1 DNA damage response pathway. The data also support the inclusion of patients with PDAC in clinical studies of 9-ING-41 alone and in combination with gemcitabine.

Original languageEnglish (US)
Pages (from-to)6452-6462
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number21
DOIs
StatePublished - Nov 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ding, L., Madamsetty, V. S., Kiers, S., Alekhina, O., Ugolkov, A., Dube, J., Zhang, Y., Zhang, J. S., Wang, E., Dutta, S. K., Schmitt, D. M., Giles, F. J., Kozikowski, A. P., Mazar, A. P., Mukhopadhyay, D., & Billadeau, D. D. (2019). Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to chemotherapy by abrogating the ToPBP1/ATR-mediated DNA damage response. Clinical Cancer Research, 25(21), 6452-6462. https://doi.org/10.1158/1078-0432.CCR-19-0799