Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Duke Researchers Describe How Breast Cancer Cells Acquire Drug Resistance

Published: Friday, May 10, 2013
Last Updated: Friday, May 10, 2013
Bookmark and Share
A seven-year quest 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.
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.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.


Scientific News
RNAi Screening Trends
Understand current trends and learn which application areas are expected to gain in popularity over the next few years.
The Genetic Roots of Adolescent Scoliosis
Scientists at the RIKEN Center for Integrative Medical Sciences in collaboration with Keio University in Japan have discovered a gene that is linked to susceptibility of Scoliosis.
A Gene-Sequence Swap Using CRISPR to Cure Haemophilia
For the first time chromosomal defects responsible for hemophilia have been corrected in patient-specific iPSCs using CRISPR-Cas9 nucleases
New Tool Uses 'Drug Spillover' to Match Cancer Patients with Treatments
Researchers have developed a new tool that improves the ability to match drugs to disease: the Kinase Addiction Ranker (KAR) predicts what genetics are truly driving the cancer in any population of cells and chooses the best "kinase inhibitor" to silence these dangerous genetic causes of disease.
Understanding the Molecular Origin of Epigenetic Markers
Researchers at IRB Barcelona discover the molecular mechanism that determines how epigenetic markers influence gene expression.
New Tech Enables Epigenomic Analysis with a Mere 100 Cells
A new technology that will dramatically enhance investigations of epigenomes, the machinery that turns on and off genes and a very prominent field of study in diseases such as stem cell differentiation, inflammation and cancer has been developed by researchers at Virginia Tech.
Access Denied: Leukemia Thwarted by Cutting Off Link to Environmental Support
A new study reveals a protein’s critical – and previously unknown -- role in the development and progression of acute myeloid leukemia (AML), a fast-growing and extremely difficult-to-treat blood cancer.
New Weapon in the Fight Against Blood Cancer
This strategy, which uses patients’ own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
Toxin from Salmonid Fish has Potential to Treat Cancer
Researchers from the University of Freiburg decode molecular mechanism of fish pathogen.
Study Finds Non-Genetic Cancer Mechanism
Cancer can be caused solely by protein imbalances within cells, a study of ovarian cancer has found.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!