Cytotoxic drugs or cytostatics are drugs used to destroy cancer cells. Cytotoxic drugs inhibit cell division and in this way cause cancer cells to die. But current treatments inevitably have negative consequences on healthy cells. Now scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill multiplying human breast cancer cells by selectively attacking the core of their cell division machinery. The method, only tested on lab-grown and patient-derived cancer cells, could advance efforts to find drugs that kill breast cancer cells in a subset of patients.
Their findings, “Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer,” were published in the journal Nature and led by Andrew Holland, PhD, associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine.
“Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer,” noted the researchers.
The research team looked for cell division mechanisms specific to cancer cells in a variety of lab-grown cells. During their search, they encountered a line of human breast cancer cells that are very dependent on cell structures called centrioles to divide and survive. A centriole is a barrel-shaped organelle which lives normally within the centrosome. The centrosome is the area of the cytoplasm. When the cell is going to divide, those centrioles go to opposite ends of the nucleus. Many cells can divide without centrioles and centrosomes. However, the researchers found that these lab-grown breast cancer cells could not.
Further observations revealed that the centriole-dependent breast cancer cells had a section of genome that had been abnormally copied many times, an alteration found in about 9% of breast cancers. The researchers observed the genes encoded in the highly copied region and found a gene that was producing high levels of a protein called TRIM37 shown to control centrosomes.
Mutations in the TRIM37 gene are associated with muscle-liver-brain-eye nanism, an autosomal recessive disorder that involves several tissues of mesodermal origin. The researchers tested a way to disrupt the cell division process in the cells with an overexpression of TRIM37.
They used a PLK4 inhibitor known to disrupt proteins that make centrioles, which interfered with TRIM37. When they added the drug to the lab-grown cancer cells with normal TRIM37 levels, they found that the cells were able to divide, even though the drug had removed the cell’s centrioles. When the drug was added to breast cancer cells with high TRIM37 levels the cells were not able to divide and most cells stopped growing or died.
“The idea would be to identify tumors with high levels of TRIM37 and use a PLK4 inhibitor to selectively kill cancer cells and leave healthy cells relatively unharmed,” explained Holland.
The Johns Hopkins and Oxford teams also discovered why high levels of TRIM37 leave cells vulnerable to drugs that remove centrioles. Holland’s previous research has shown that normal cells can divide without centrioles, because the material around the centriole, called the pericentriolar material, is able to do the same job as centrosomes. In the most recent study, the research team discovered that high levels of TRIM37 cause cells to degrade pericentriolar material. Meaning by adding a drug that removes centrioles, the cells have no choice but to organize the tubes that help divide the DNA during cell division.
“Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers,” concluded the researchers.
Looking forward, the research team is exploring more stable drugs similar to the PLK4 inhibitor used in the current study and attempting to identify additional human cancer cell lines that are sensitive to these inhibitors.