Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Duke researchers describe how breast cancer cells acquire drug resistance

08.05.2013
A seven-year quest to understand how breast cancer cells resist treatment with the targeted therapy lapatinib has revealed a previously unknown molecular network that regulates cell death. The discovery provides new avenues to overcome drug resistance, according to researchers at Duke Cancer Institute.

"We've revealed multiple new signaling pathways that regulate cell death," said Sally Kornbluth, PhD, vice dean of Basic Science and professor of Pharmacology and Cancer Biology at Duke University School of Medicine. "And we've shown, at least in one disease, these signaling pathways can go awry in drug resistance. It also suggests you could manipulate these other pathways to overcome drug resistance."

The researchers -- co-directed by Kornbluth and Neil Spector, M.D., associate professor of medicine at Duke -- identified a protein that effectively shuts down the signals that tell a cell to die, enabling cancer cells to keep growing. That protein, MDM2, is already generating intense interest in the cancer research community because it is a master regulator of the tumor suppressor protein called p53.

Findings are published in the May 7, 2013, issue of the journal Science Signaling.

The Duke research team, with assistance from collaborators at the University of Michigan, identified a new role for MDM2 in activating cell death pathways independent of its role in regulating p53, a known initiator of cell death. More than half of all human tumors contain a mutation or deletion of the gene that controls p53.

The researchers began by studying four different types of breast cancer cells that were able to keep growing despite treatment with lapatinib, a powerful drug that targets two growth pathways commonly disrupted in breast cancer, HER2 and epidermal growth factor receptor. They found that in each case, the drug resistance could be traced to the presence of high levels of MDM2, which was found to be 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. Researchers at Duke, including the Spector laboratory, and other investigators 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 for the Cure foundation has provided research support into lapatinib resistance. A full list of funders is provided in the published manuscript.

The authors have filed a patent application based on this work. Shaomeng Wang owns stocks and is a consultant for Ascenta, and is a co-inventor on MI-219 and related MDM2 inhibitors. Ascenta has licensed MI-219 and related MDM2 inhibitors from the University of Michigan to Sanofi for clinical development.

Sarah Avery | EurekAlert!
Further information:
http://www.duke.edu

More articles from Health and Medicine:

nachricht One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center

nachricht The gut microbiota plays a key role in treatment with classic diabetes medication
01.06.2017 | University of Gothenburg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>