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Duke researchers describe how breast cancer cells acquire drug resistance
Date:5/7/2013

blocking cell death signals independent of whether p53 was activated.

"These results suggest that inhibition of MDM2, at least in the setting of breast cancer, might overcome lapatinib resistance even if p53 is mutated," Kornbluth said.

Spector and his colleagues first reported the activation of estrogen receptor signaling, which led to FDA-approval of lapatinib in combination with letrozole as a first-line treatment for advanced-stage HER2-positive and estrogen receptor-positive breast cancers. Several research teams at Duke, including Spector's laboratory, have worked to identify various mechanisms of lapatinib resistance.

"The importance of this new MDM2 finding is that it may underlie these proposed mechanisms of resistance and therefore provide a more effective treatment," Spector said.

The findings also suggest that other drugs targeting tyrosine kinases may be vulnerable to resistance using this same mechanism. Gefitinib is a targeted cancer therapy that blocks a tyrosine kinase enzyme to treat non-small cell lung cancers caused by mutations in the epidermal growth factor receptor.

"This study raises the possibility that resistance to other tyrosine kinase inhibitor drugs, such as gefitinib-resistant lung cancer, could involve MDM2," Kornbluth said. "We are now going to investigate whether MDM2 has anything to do with gefitinib resistance."

The lead author of the paper, Manabu Kurokawa, is now an assistant professor at Dartmouth University. Other authors of the paper include Jiyeon Kim, Joseph Geradts, Kenkyo Mastuura, Wenle Xia, Thomas J. Ribar, Ricardo Henao, Neil L. Spector, Mark W. Dewhirst, and Joseph E. Lucas of Duke; Wun-Jae Kim of Chungbuk National University Hospital; and Shaomeng Wang, Liu Liu, and Xu Ran of the University of Michigan.

The study was funded in part by the National Institutes of Health (R01 CA102707) and the National Cancer Institute (K99 CA140948). The Susan G. Komen f
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Contact: Sarah Avery
sarah.avery@duke.edu
919-660-1306
Duke University Medical Center
Source:Eurekalert

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