Therapeutic Targeting of Cancer Stem Cells Prevents Resistance of Colorectal Cancer Cells to MEK Inhibition

Abstract

Drug resistance is a leading cause for the failure of cancer treatments. Plasticity of cancer cells to acquire stem cell-like properties enables them to escape drug toxicity through different adaptive mechanisms. Eliminating cancer stem cells (CSCs) can potentially improve treatment outcomes for patients. To determine the role of CSCs in resistance of colorectal cancer cells to targeted therapies and identify treatment strategies, we treated spheroids of BRAFmut and KRASmut colorectal cancer cells with inhibitors of the mitogen-activated protein kinase pathway and studied resistance mechanisms through gene and protein expression analyses. We found that treatments activated several oncogenic pathways and expression of CSC markers CD166 and ALDH1A3. We identified a specific combination treatment using trametinib and mithramycin A to simultaneously inhibit the CSC phenotype and activities of several pathways in cancer cells. This study demonstrates the feasibility of therapeutic targeting of CSCs as a strategy to block tumorigenic activities of cancer cells.

Ku70 senses cytosolic DNA and assembles a tumor-suppressive signalosome

“…Organoids cultured from Apc Min/+ mice had increased expression of Ctnnb1 , Axin2 , and Lgr5 following treatment with the MEK inhibitor U0126 as compared to the vehicle control (fig. S20H), consistent with previous studies ( 51 , 52 ).…”

“…Organoids cultured from Apc Min/+ mice had increased expression of Ctnnb1, Axin2, and Lgr5 following treatment with the MEK inhibitor U0126 as compared to the vehicle control (fig. S20H), consistent with previous studies (51,52). Ku70 senses cytosolic DNA and forms a signalosome at the endosome Previous studies have shown that patients with ulcerative colitis have more nuclear-and mitochondria-free (cell-free) DNA in the plasma than healthy controls (53,54).…”

“…Together, these results indicate that dabrafenib-mediated inhibition of Raf might reduce the binding strength between Ras with Raf, and between Ku70 and Ras, which in turn might affect the signaling of the Ku70-Ras-Raf complex. Previous studies have shown that MEK inhibitors reduce cell proliferation but increase the expression of genes such as Ctnnb1 , Axin2 , and Lgr5 , which are highly associated with cancer development ( 51 , 52 ). Organoids cultured from Apc Min/+ mice had increased expression of Ctnnb1 , Axin2 , and Lgr5 following treatment with the MEK inhibitor U0126 as compared to the vehicle control (fig.…”

“…Inhibitors of MEK have also been tested as potential therapeutics for the treatment of colorectal cancer; however, their efficacy is limited because of the paradoxical activation of ERK ( 57 , 91 ). Moreover, previous studies have shown that MEK inhibition using trametinib promotes the expression of genes associated with cancer development ( 51 , 52 ). Furthermore, small-molecule inhibitors of ERK either show no efficacy or produce a partial clinical response in patients with KRAS- and BRAF-mutant colorectal cancer ( 91 ).…”

Differential Expression of SRY-Related HMG-Box Transcription Factor 2, Oligodendrocyte Lineage Transcription Factor 2, and Zinc Finger E-Box Binding Homeobox 1 in Serum-Derived Extracellular Vesicles: Implications for Mithramycin Sensitivity and Targeted Therapy in High-Grade Glioma

“…Mithramycin (Mit-A), an antineoplastic antibiotic known to inhibit RNA synthesis and produced by Streptomyces plicatus, is one such promising compound . Mit-A has been shown to have antitumor effects by targeting cancer stem cells in various cancers. − Mit-A has demonstrated significant inhibition of GBM invasiveness by targeting the GSC transcription factors SOX2, OLIG2, and ZEB1 in glioma . Additionally, Mit-A treatment reduced cell migration in gliomas by altering MMP-2 and 9, VEGF, and RON kinase .…”