Using a functional genomic screen, scientists have identified individual genes that are associated with resistance to chemotherapeutic drugs.
Researchers from the Cancer Research UK London Research Institute used RNAi to directly examine the contribution of over 800 candidate proteins to the sensitivity or resistance of cancer cells to several drugs that are commonly used to treat cancer.
Using this technique, the researchers found that resistance to the chemotherapeutic agent paclitaxel involves genes that impair drug-induced mitotic arrest following knockdown. Silencing of these genes in many cases also induces polyploidy and multinucleation in the absence of drug treatment. The researchers conclude that specific disruption of the mitotic checkpoint promotes paclitaxel resistance and that chromosomal numerical heterogeneity may be a useful predictor of paclitaxel resistance in some cancers.
The researchers identified ceramide metabolism as a critical regulator of sensitivity to a wide range of chemotherapeutic drugs. Although ceramide has been associated with apoptosis for some time, the mechanisms have not been well understood. In this study, decreased expression of a ceramide transport protein, COL4A3BP, sensitized cancer cells to multiple cytotoxic agents. Further, expression of COL4A3BP was increased in drug-resistant tumor cells and in a small cohort of ovarian cancers following paclitaxel treatment.
The researchers suggest that paclitaxel-induced, prolonged mitotic arrest may result in ceramide accumulation and initiation of apoptosis, while inhibition of this arrest, characterized by polyploidy, may suppress ceramide generation and promote cell survival.
The research is published in the June issue of Cancer Cell.