"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!
Scientists develop tiny tooth-mounted sensors that can track what you eat
22.03.2018 | Tufts University
NIH scientists describe potential antibody treatment for multidrug-resistant K. pneumoniae
14.03.2018 | NIH/National Institute of Allergy and Infectious Diseases
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
22.03.2018 | Trade Fair News
22.03.2018 | Earth Sciences
22.03.2018 | Earth Sciences