Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study identifies mechanism of resistance to targeted therapy in lung cancer patients

24.02.2005


Findings help explain how cancer cells develop resistance to gefitinib



A new study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) identifies a second mutation in a gene associated with non-small-cell lung cancer (NSCLC), a discovery that helps to explain why NSCLC tumors become resistant to treatment with the cancer therapy gefitinib (Iressa).

The findings, which are reported in the February 24, 2005 issue of The New England Journal of Medicine (NEJM), could help lead to the development of second-generation inhibitor drugs to treat NSCLC, which accounts for approximately 85 percent of all lung cancer cases and is the leading cause of death from cancer in the U.S. among both men and women.


One of a new generation of cancer therapies that work by disrupting the specific molecular target responsible for stimulating tumor growth, gefitinib acts on the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells. In 2003, it was approved by the U.S. Food and Drug Administration as a treatment for NSCLC.

Clinical applications of the new drug initially yielded very good results, with approximately 10 percent of patients experiencing complete remission of their disease. Two separate studies published last year in NEJM and Science offered an explanation for how this was happening, suggesting that a mutation in the EGFR gene of these individuals was causing their cancer cells to produce abnormal versions of growth signals called tyrosine kinases. Among these patients, gefitinib works by snugly fitting into the activating pocket of the protein like a key into a keyhole, blocking the growth signals and thereby depriving the cancer cells of the stimuli they need to survive and proliferate.

However, in spite of the therapy’s initial success, patients inevitably suffered a relapse and their tumors started to grow again. "It appeared that the tumors in these patients had found a way to bypass the effects of gefitinib," explains the study’s last author Balazs Halmos, MD, a physician-scientist formerly at BIDMC and presently with the Ireland Cancer Center, University Hospitals of Cleveland. To detemine if this was indeed the case, Halmos identified a 71-year-old patient with advanced NSCLC whom he had been treating at BIDMC, and who had recently relapsed after two years of complete remission while undergoing gefitinib therapy.

Hypothesizing that the relapse may have been due to another mutation in the EGFR gene which was causing cancer cells to become resistant to the drug, Halmos, together with the study’s corresponding author Daniel Tenen, MD, a molecular biologist in the Division of Hematology/Oncology at BIDMC, and Susumu Kobayashi, MD, PhD, a physician-scientist in Tenen’s laboratory, obtained a second biopsy of the tumor and resequenced the EGFR tyrosine kinase domain.

Their studies confirmed the existence of a second mutation, and insertion of this mutation into test cells rendered them resistant to gefitinib in vitro. Further analysis revealed that the newly identified mutation was altering gefitinib’s drug-binding pocket and thereby changing the "keyhole" so that the "key" – gefitinib – no longer fit. "The development of a second mutation suggests that the tumor cells remain dependent on an active EGFR pathway for their proliferation," explains Tenen, who is also a Professor of Medicine at Harvard Medical School. "This mirrors the situation that developed over the past few years among patients with chronic myeloid leukemia and gastrointestinal stromal tumors who were being treated with imatinib [Gleevec]." In those cases, he adds, the identification of mechanisms of resistance helped lead to the development of second-generation inhibitor drugs now being clinically tested.

And in fact, according to study coauthor Bruce Johnson, MD, Director of the Dana-Farber/Harvard Cancer Center Lung Program, clinical investigators are already moving in this direction. "Our preliminary results have yielded encouraging findings, pointing towards drugs that might bypass this method of resistance," says Johnson. "We’re now in the process of planning clinical studies to test novel EGFR inhibitor compounds in lung-cancer patients whose tumors have become resistant to gefitinib."

The results may also lead to new diagnostic methods.

"I believe that findings like these will hasten the use of molecular oncology for everyday practice," says Tenen. "Analogous to the way that antibiotic and antiviral regimens might be selected today based on the results of microbiological testing, I can certainly envision a time in the future when molecular monitoring for mutations and drug regimens will be adjusted based on these results."

In addition to Halmos, Tenen, Kobayashi and Johnson, study coauthors include BIDMC investigators Olivier Kocher, MD, PhD, and Tajhal Dayaram, BA; and Dana-Farber Cancer Institute investigators Titus Boggon, PhD, Michael Eck, MD, PhD, Pasi Janne, MD, PhD, and Matthew Meyerson, MD, PhD.

Bonnie Prescott | EurekAlert!
Further information:
http://www.bidmc.harvard.edu

More articles from Studies and Analyses:

nachricht Drone vs. truck deliveries: Which create less carbon pollution?
31.05.2017 | University of Washington

nachricht New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)

All articles from Studies and Analyses >>>

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

New 3-D model predicts best planting practices for farmers

26.06.2017 | Agricultural and Forestry Science

New research reveals impact of seismic surveys on zooplankton

26.06.2017 | Life Sciences

Correct connections are crucial

26.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>