GSE184125
9-ING-41, a small molecule inhibitor of GSK-3ß, potentiates the effects of chemotherapy in KRAS mutated colorectal cancer
Despite the prevalence of KRAS mutations in colorectal cancer, there is no K-Ras targeted therapies for these tumors and available treatment options are limited for metastatic disease. GSK-3ß has been demonstrated to be a critically important kinase for survival and proliferation of K-Ras-depended pancreatic cancer cells. In this study we tested 9-ING-41, a small molecule inhibitor of GSK-3ß, in patient-derived tumor organoid models of colorectal cancer. We demonstrated that addition of 9-ING-41 to the standard of care drugs 5-FU and oxaliplatin could significantly enhance inhibition of the growth of colorectal cancer cells harboring KRAS mutations. 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. Moreover, we found substantial similarity in the changes of transcriptomic profile after inhibition of GSK-3ß and suppression of STK33, another critically important kinase for K-Ras-dependent cells. Overall, the results of this study provide a rationale for the inclusion of patients with mutant KRAS colorectal cancer in clinical studies of 9-ING-41 and other GSK-3 inhibitors. Overall design: Total mRNA profiles of 9-ING-41 treated and control colorectal tumor organoids.