Scientists Discover Gene that Appears to Permanently Halt Cancer Cell Propagation

Through their studies of the molecular mechanisms involved in DNA repair, scientists from Case Western Reserve University School of Medicine found that the artificial activation of a gene called Chk1 permanently halts cancer cell replication.

Researchers have discovered that the mutant form of the gene Chk1, when expressed in cancer cells, halts cell proliferation and causes apoptosis—even in the absence of toxic chemotherapeutic drugs.

Researcher Youwei Zhang, PhD, assistant professor in the Department of Pharmacology at Case Western Reserve University School of Medicine, and colleagues happened upon the mutant form of Chk1 while studying the molecular mechanisms of the genomic pathways involved in DNA repair. The mutant form of the “checkpoint” protein kinase Chk1 facilitates cell survival by pausing cell cycle progression and coordinating DNA repair processes. Investigators noted that activation of the mutant form of this gene permanently stopped the cancer cells from growing.

Chk1 works by protecting against replicative stress, a kind of damage that can occur during mitosis. It is often referred to as a “genome guardian.” The normal, nonmutant form of Chk1, when overexpressed, has been shown in prior studies to have a negative effect—cells become malignant more easily, because Chk1 can have a protective effect on tumors once the growths have established themselves in the body.

Although the function of mutant Chk1 was only studied in petri dishes, and its effectiveness has not yet been observed in human trials, the idea of combining a Chk1 inhibitor with chemotherapy or radiotherapy is a novel treatment method that may drive future drug development.

“We have identified a new direction for cancer therapy and the new direction is leading us to a reduction in toxicity in cancer therapy, compared with chemotherapy or radiation therapy,” said Dr. Zhang in a press release. “With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.”

In order to fully activate Chk1 in cancer cells, Dr. Zhang and colleagues plan to explore both gene therapy and small molecule therapies to induce mutation of the Chk1 gene and stop tumor growth. Some Chk1 inhibitors have already been tested in drug trials in combination with Gemcitabine in patients with advanced solid tumor malignancies or lymphoma (non-Hodgkin's or Hodgkin's lymphoma), but none of these formulations have passed Phase III clinical trials.

The study was supported by the National Cancer Institute at the National Institute of Health and was published in the journal Cancer Research.