Signaling pathways related to cancer stem cells (CSCs) and mutations within stem cells (SCs). In the Wnt signaling pathway, Disheveled (DVL) is activated, leading to the inhibition of GSK3β, which occurs after Wnt binds to its receptors. This process stabilizes β-catenin, allowing it to translocate into the nucleus, where it interacts with transcription factors TCF/LEF to initiate the expression of target genes, thereby promoting CSC renewal. In the Sonic Hedgehog (Shh) pathway, the receptor Patched (PTCH) activates Smoothened (SMO) in response to Shh ligand binding. This activation results in the accumulation of GLI1 in the nucleus, where it induces the expression of genes that confer tumorigenic properties to cancer cells. In the BMI-1 pathway, the expression of BMI-1 is regulated by various factors: Notch, MYC, SALL4, and Nrf2 are upregulated, while miR-200c and Mel-18 downregulate BMI-1. BMI-1 influences CSC differentiation by repressing Hox genes and controls cell proliferation and malignancy by inhibiting the Ink4a/Arf gene locus. In the PI3K/AKT pathway, mutations in the PIK3CA gene lead to the production of the p110α protein, which catalyzes the activation of PI3K. PI3K then phosphorylates AKT1 by converting PIP2 to PIP3, subsequently activating PDK1 and contributing to oncogenic transformation.

The success of cancer therapy has been significantly hampered by various mechanisms of therapeutic resistance. Chief among these mechanisms is the presence of clonal heterogeneity within an individual tumor mass. The introduction of the concept of cancer stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding of drug resistance. Given the characteristics of CSCs, such as increased drug-efflux activity, enhanced DNA-repair capacity, high metabolic plasticity, adaptability to oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have been recognized as a theoretical reservoir for resistant diseases. Implicit in this recognition is the possibility that CSC-targeted therapeutic strategies might offer a breakthrough in overcoming drug resistance in cancer patients. Herein, we summarize the generation of CSCs and our current understanding of the mechanisms underlying CSC-mediated therapeutic resistance. This extended knowledge has progressively been translated into novel anticancer therapeutic strategies and significantly enriched the available options for combination treatments, all of which are anticipated to improve clinical outcomes for patients experiencing CSC-related relapse.

Article Access: https://doi.org/10.1002/mog2.70009

More about MedComm-Oncology: https://onlinelibrary.wiley.com/journal/27696448

Looking forward to your contributions.