Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mechanism of lung cancer-associated mutations suggests new therapeutic approaches

31.07.2012
Vanderbilt-Ingram Cancer Center researchers have identified how one of the genes most commonly mutated in lung cancer may promote such tumors.

The investigators found that the protein encoded by this gene, called EPHA3, normally inhibits tumor formation, and that loss or mutation of the gene – as often happens in lung cancer – diminishes this tumor-suppressive effect, potentially sparking the formation of lung cancer.

The findings, published July 24 in the Journal of the National Cancer Institute, could offer direction for personalizing cancer treatments and development of new therapies.

The ephrin family of receptors (EPH receptors) comprises a large group of cell surface proteins that regulate cell-to-cell communication in normal development and disease. EPH receptor mutations have been linked to several different cancer types.

Jin Chen, M.D., Ph.D., professor of Medicine, Cancer Biology and Cell & Developmental Biology, studies the cancer-associated roles of these receptors. While her lab has focused primarily on EPHA2 (and its role in promoting breast cancer and tumor blood vessel formation), she decided to look at a different ephrin receptor based on the findings of large genomic screens of lung tumors.

"A 2008 genome-wide study published in Nature identified 26 genes as potential drivers of lung cancer," Chen said. "One of them was EPHA3."

That study and others suggested that mutations in EPHA3 were present in 5 percent to 10 percent of lung adenocarcinomas. However, the studies did not reveal how these mutations might promote tumor formation or progression.

Chen wanted to investigate further whether mutations in EPHA3 were actually "drivers" of lung cancer or just neutral "passenger" mutations and how the mutations might promote tumor growth.

The researchers generated and analyzed 15 different mutations in the receptor. They found that at least two functioned as "dominant negative" inhibitors of the EPHA3 protein – that is, having a mutation in just one allele (or "copy" – humans have two copies of each gene) was enough to inhibit the function of EPHA3.

Chen and colleagues determined that normal or "wild type" EPHA3 inhibits a downstream signaling pathway (the Akt pathway) that promotes cell survival – so, normally, activation of EPHA3 acts as a "brake" on cell growth and survival and induces programmed cell death (apoptosis). When one EPHA3 allele is lost (due to a mutation), the receptor cannot be activated and the Akt pathway remains active, which promotes cell growth and survival.

To determine the impact of EPHA3 mutations on human lung cancer cases, biostatisticians Yu Shyr, Ph.D., and Fei Ye, Ph.D., helped Chen's group identify a mutational signature from existing patient data that strongly correlated with poor patient survival. The team also found that both gene and protein levels of EPHA3 were decreased in patient lung tumors.

While previous studies had linked EPHA3 mutations to lung cancer, the current study is the first to "connect the dots."

"The EPH family is such a big family that nobody had really connected the data from bench top – from the cell and biochemical studies – to human data," Chen said.

Together, the findings suggest that mutations in EPHA3 may be important drivers of a significant fraction of lung cancers. And the research team's identification of the biochemical and cellular consequences of EPHA3 mutations suggests that therapies that target a downstream pathway (such as Akt) might be beneficial for tumors with mutant EPHA3.
Shyr is a professor of Biostatistics, Cancer Biology and Preventive Medicine and is Director of the Center for Quantitative sciences; Ye is an assistant professor of Biostatistics.

The research was supported by grants from the National Cancer Institute (CA095004, CA114301, CA117915, CA009592, CA090949) of the National Institutes of Health, the Department of Veterans Affairs and the Department of Defense.

Melissa Stamm | EurekAlert!
Further information:
http://www.vanderbilt.edu

More articles from Health and Medicine:

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

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: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>