Researchers at Case Western Reserve University School of Medicine, Cleveland, have discovered a mutant form of the gene Chk1 that when expressed in cancer cells, permanently stopped their proliferation and caused cell death without the addition of any chemotherapeutic drugs.1 This study illustrates an unprecedented finding: that artificially activating Chk1 alone is sufficient to kill cancer cells.
“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 Youwei Zhang, PhD, Assistant Professor, Department of Pharmacology at the School of Medicine, and member of the university’s Case Comprehensive Cancer Center. “With this discovery, scientists could stop the proliferation of cancer cells, allowing physicians time to fix cells and genetic errors.”
While studying the basic mechanisms for genome integrity, Dr. Zhang’s team unexpectedly discovered an active mutant form of human Chk1, which is also a nonnatural form of this gene. This mutation changed the protein conformation of Chk1 from the inactive form into an active form. Remarkably, the research team discovered that when expressed in cancer cells, this active mutant form of Chk1 permanently stopped cancer cell proliferation and caused cell death in petri dishes even without the addition of any chemotherapeutic drugs.
The biggest advantage of this potential strategy is that no toxic chemotherapeutic drug is needed to achieve the same cancer killing effect used with a combination of Chk1 inhibitors and chemotherapeutic drugs.
Cells respond to DNA damage by activating networks of signaling pathways, termed cell-cycle checkpoints. Central to these genome pathways is the protein kinase, called Chk1. Chk1 facilitates cell survival, including cancer cells, under stressful conditions, such as those induced by chemotherapeutic agents, by placing a temporary stop on the cell-cycle progression and coordinating repair programs to fix the DNA errors. ■
1. Wang J, Han X, Zhang Y: Autoregulatory mechanisms of phosphorylation of checkpoint kinase 1. Cancer Res 72:3786-3794, 2012.