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Cancer drug target Chk1 may also be source of drug resistance


New findings suggest balancing Chk1 activity will produce less toxic cancer drugs

A study published by The Burnham Institute in the September edition of Molecular Cell reports that a cell-cycle checkpoint protein, known to be activated by an important class of anticancer drugs, may play crucial roles in both the hampering of therapeutic actions and aiding cancer cells to "recover" and start dividing again after treatment with these drugs. The study is expected to help academic researchers and biotechnology and pharmaceutical companies design drugs that combat cancer using this checkpoint protein, but with fewer side effects.

Robert Abraham, Ph.D., former director of The Burnham Institute’s Cancer Center and now vice president for oncology research at Wyeth Pharmaceuticals, together with his colleagues, found that the Chk1 protein responds with cell-survival activity to stressful conditions induced by hypoxia and certain anticancer drugs. Furthermore these same conditions target Chk1 for eventual destruction. Ironically, stimulation of Chk1 triggers certain repair responses that fight cancer while the simultaneous degradation of Chk1 can allow cancer cells to escape drug-induced death and resume progressive tumor growth.

The study suggests the Chk1 protein is critical for ensuring the repair of mutations and other errors in DNA replication before they can alter the function of a cell. If not repaired, these errors can kill the cell when it attempts to divide and proliferate. In cancer cells, Chk1 is responds as a natural defense to the therapeutic damage done by radiation and chemotherapy and attempts to effect repair to DNA damage caused by the cancer therapy, thus makes the drug therapy less effective.

The researchers also found that the chemotherapy agent campthothecin (CPT), a clinically important anticancer agent, reduced the activity of the Chk1 protein. "These findings lend strong support to the idea that inactivation of Chk1 contributes to the antitumor activity of CPT by allowing cells bearing damaged DNA to progress through the cell cycle, leading to an unsuccessful and often lethal attempt to undergo cell division," said Abraham. "Combination therapy, which pairs a chemotherapy agent with an inhibitor of Chk1, may therefore be an effective strategy to increase the efficacy of certain anticancer drugs, and may well overcome clinical resistance to these drugs."

By studying the effects of radiation and other stresses on the pathway that normally regulate Chk1, the researchers discovered that the same pathway that activates Chk1 via phosphorylation by its regulatory enzyme, ATR, also marks Chk1 for eventual destruction.

"We expect this process prevents activated Chk1 from accumulating in normal cells and prevents abnormal cell proliferation," said Abraham. "ATR activates, but also destabilizes Chk1, which creates a homeostatic mechanism that balances the genome protective function of Chk1 with the process of cell proliferation. This is a new look at drug therapy. Textbook descriptions of ATR and Chk1 don’t describe this dual role."

"The findings also provide further insight into Chk1 activation and tumor sensitivity," Abraham added. "Cancer cells rely heavily on Chk1 for survival and proliferation under stressful environmental conditions. Instead of halting abnormal growth of cancer cells, drug therapy could in effect induce Chk1 natural activity to prevent cell death in cancer cells."

Collaborators on this publication include You-wei Zhang, Diane M. Otterness, and Gary Chiang from Dr. Abraham’s laboratory at The Burnham Institute; and Weilin Xie, and Franklin Mercurio of Celgene Corporation; and Yun-Cai Liu of La Jolla Institute for Allergy and Immunology.

Nancy Beddingfield | EurekAlert!
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