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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.777114

DOI=10.3389/fphar.2021.777114

ISSN=1663-9812

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 has been demonstrated to be a critically important kinase for the survival and proliferation of K-Ras-depended 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 colorectal cancer cell lines and patient-derived tumor organoid models of colorectal cancer. We demonstrated that 9-ING-41 inhibits the growth of colorectal cancer 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 colorectal cancer cells. Notably, we found 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, that could 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.