9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

Andrey Poloznikov, Sergey Nikulin, Larisa Bolotina, Andrei Kachmazov, Maria Raigorodskaya, Anna Kudryavtseva, Ildar Bakhtogarimov, Sergey Rodin, Irina Gaisina, Maxim Topchiy, Andrey Asachenko, Victor Novosad, Alexander Tonevitsky, Boris Alekseev

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Abstract

Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

Original languageEnglish
Article number777114
JournalFrontiers in Pharmacology
Volume12
DOIs
StatePublished - 9 Dec 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2021 Poloznikov, Nikulin, Bolotina, Kachmazov, Raigorodskaya, Kudryavtseva, Bakhtogarimov, Rodin, Gaisina, Topchiy, Asachenko, Novosad, Tonevitsky and Alekseev.

Funding

This work was financially supported by the Russian Science Foundation (Project No. 19-15-00397) and in part (bioinformatic analysis) by HSE University Basic Research Program.

FundersFunder number
Russian Science Foundation19-15-00397
National Research University Higher School of Economics

    Keywords

    • 9-ING-41
    • GSK-3
    • KRAS
    • cell cycle
    • colorectal cancer
    • tumor organoids

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