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Impact of elraglusib (9-ING-41) treatment on gene expression in human colorectal cancer and immune cell lines.

ABSTRACT: Impact of elraglusib (9-ING-41) treatment on gene expression in human colorectal cancer and immune cell lines.

PROVIDER: PRJNA923655 | ENA |

REPOSITORIES: ENA

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Impact of elraglusib (9-ING-41) treatment on gene expression in human colorectal cancer and immune cell lines.

Project description:A growing body of literature evaluates the potential anti-cancer and immunostimulatory effects of GSK-3 inhibition. Accordingly, we sought to evaluate GSK-3 inhibitor elraglusib (9-ING-41) and its impact on gene expression in both human colorectal cancer (CRC) cell lines and human immune cell lines. We used microarrays to detail the differential gene expression that occurs post-treatment with GSK-3 inhibitor 9-ING-41 (elraglusib).

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

Project description: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.

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