Identification of a Selective Small-Molecule Inhibitor of Breast Cancer Stem Cells - Probe 1

Review
In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010.
[updated ].

Excerpt

Cancer stem cells (CSCs), which drive tumor growth, are known to be resistant to standard chemotherapy and radiation treatment. This raises a significant unmet need to find therapies that can target CSCs within tumors because these cells are responsible for recurrence, the primary cause of patient mortality. However, one of the challenges is that CSCs are not stable outside the tumor environment and are not easy to grow in culture media. Hence, stable sibling cell lines that were induced into epithelial-to-mesenchymal transdifferentiation (EMT) to stably propagate CSC-enriched populations were used to screen a library of 300,718 compounds from the Molecular Libraries Small Molecule Repository (MLSMR). Several classes of selective inhibitors of CSCs were identified. The use of isogenic control cell lines for the secondary validation assays minimized the probability of false hits advancing along the critical path to probe development. Of these, 19 compounds were chosen based on their selectivity, potency, and chemical tractability and were retested in the primary screen and secondary assays. Three scaffolds were prioritized to identify potential probes. One of these compounds (ML239) displayed greater than 23-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_GFP). This probe did not significantly inhibit tumorsphere formation in the breast cancer cell line SUM159, which is a mixture of CSCs and differentiated cells. However, analogs that inhibited both cell types (HMLE_sh_Ecad and HMLE_sh_GFP) could suppress tumorsphere formation, suggesting that suppression of both cell types may be needed to inhibit tumorsphere formation in the SUM159 cancer cell line. Gene expression experiments where HMLE_sh__Ecad cells were treated with the probe (ML239) identified protein processing genes in the endoplasmic reticulum (ER) (i.e., Sels, HSPAS, ATF4, GADD23, and HERPUD1), Ras-mitogen-activated protein kinase (MAPK) signaling (i.e., CREB2(ATF-4); GADD153), and inflammatory cytokine expression/signaling pathways (i.e., IL-6) as having altered expression after treatment with the probe. Only five genes had significantly altered gene expression changes after 24-hour treatment with the probe in the HMLE_sh_GFP cell line. This further supports the finding that we have identified a selective probe that targets breast CSC-like cells. This new probe should be useful in future, cell-based investigations and in vivo studies of breast cancer models as well as target identification studies.

Publication types

  • Review