Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis

Abstract

Despite advances in treatment, cancer remains the 2nd most common cause of death in the United States. Poor cure rates may result from the ability of cancer to recur and spread after initial therapies have seemingly eliminated detectable signs of disease. A growing body of evidence supports a role for cancer stem cells (CSCs) in tumor regrowth and spread after initial treatment. Thus, targeting CSCs in combination with traditional induction therapies may improve treatment outcomes and survival rates. Unfortunately, CSCs tend to be resistant to chemo- and radiation therapy, and a better understanding of the mechanisms underlying CSC resistance to treatment is necessary. This paper provides an update on evidence that supports a fundamental role for CSCs in cancer progression, summarizes potential mechanisms of CSC resistance to treatment, and discusses classes of drugs currently in preclinical or clinical testing that show promise at targeting CSCs.

Figure 1

Cell surface phenotype of cancer stem cells. A summary of cancer stem cells surface markers identified in a variety of cancer types.

Figure 2

Schematic diagram of the mechanisms leading to cancer stem cell resistance to chemo- and radiation therapy. Cancer stem cells have been found to exhibit a number of genetic and cellular adaptations that confer resistance to classical therapeutic approaches, including relative dormancy/slow cell cycle kinetics, efficient DNA repair, high expression of multidrug-resistance-type membrane transporters, resistance to apoptosis, and protection by a hypoxic niche environment.

Figure 3

Schematic diagram of the canonical Wnt/β-catenin signaling. Wnt/β-catenin pathway may promote genomic instability after irradiation, thus allowing tumor cells to both survive after irradiation and develop additional adaptive mutations. ICG-001, PKF115-854, and CGP049040 are anticancer drugs in development that target the Wnt signaling pathway.

Figure 4

Schematic diagram of the Notch signaling pathway. The Notch/γ-secretase/Jagged signaling pathway is an important regulator of differentiation and helps specify cell fate. Notch signaling pathways have been shown to be activated in both breast CSCs and in endothelial cells in response to radiation. MK-0752 and R4733 are drugs under development targeting γ-secretase in this signaling pathway.

Figure 5

Schematic diagram of the Sonic Hedgehog signaling pathway. The hedgehog signaling pathway is a potential modulator of cancer stem cell carcinogenesis with significant therapeutic implications. GDC-0449, XL-139, and IPI-926 are drugs under development targeting this signaling pathway.