Cancer Drug Target Chk1 May Also Be Source Of Drug Resistance

Robert Abraham, Ph.D., former director of The Burnham Institute'sCancer Center and now vice president for oncology research at WyethPharmaceuticals, together with his colleagues, found that the Chk1protein responds with cell-survival activity to stressful conditionsinduced by hypoxia and certain anticancer drugs. Furthermore these sameconditions target Chk1 for eventual destruction. Ironically,stimulation of Chk1 triggers certain repair responses that fight cancerwhile the simultaneous degradation of Chk1 can allow cancer cells toescape drug-induced death and resume progressive tumor growth.

The study suggests the Chk1 protein is critical for ensuring the repairof mutations and other errors in DNA replication before they can alterthe function of a cell. If not repaired, these errors can kill the cellwhen it attempts to divide and proliferate. In cancer cells, Chk1 isresponds as a natural defense to the therapeutic damage done byradiation and chemotherapy and attempts to effect repair to DNA damagecaused by the cancer therapy, thus makes the drug therapy lesseffective.

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

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

"We expect this process prevents activated Chk1 from accumulating innormal cells and prevents abnormal cell proliferation," said Abraham."ATR activates, but also destabilizes Chk1, which creates a homeostaticmechanism that balances the genome protective function of Chk1 with theprocess 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 andtumor sensitivity," Abraham added. "Cancer cells rely heavily on Chk1for survival and proliferation under stressful environmentalconditions. Instead of halting abnormal growth of cancer cells, drugtherapy could in effect induce Chk1 natural activity to prevent celldeath in cancer cells."

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

This work was supported by grants from Johnson & Johnson, theNational Institutes of Health, the Department of Defense Breast CancerResearch Program, a postdoctoral training grant from the Susan G. KomenBreast Cancer Foundation, and a Kirschstein-NRSA fellowship.

The Burnham Institute, founded in 1976, is an independentnot-for-profit biomedical research institution dedicated to advancingthe frontiers of scientific knowledge and providing the foundation fortomorrow's medical therapies. The Institute is home to three majorcenters: the Cancer Center, the Del E. Webb Neuroscience and AgingCenter, and the Infectious and Inflammatory Disease Center. Since 1981,the Institute's Cancer Center has been a member of the National CancerInstitute's prestigious Cancer Centers program. Discoveries by Burnhamscientists have contributed to the development of new drugs forAlzheimer's disease, heart disease and several forms of cancer. Todaythe Burnham Institute employs over 700, including more than 550scientists. The majority of the Institute's funding derives fromfederal sources, but private philanthropic support is essential tocontinuing bold and innovative research. For additional informationabout the Institute and ways to support the research efforts of theInstitute, visit www.burnham.org.