Mechanism of lung cancer-associated mutations suggests new therapeutic approaches
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.
Journal reference: Journal of the National Cancer Institute
Provided by Vanderbilt University Medical Center
- New target identified for squamous cell lung cancer Apr 03, 2011 | not rated yet | 0
- The link between TB and a gene mutation that causes lung cancer Jan 18, 2012 | not rated yet | 0
- KRAS gene mutation and amplification status affects sensitivity to antifolate therapy Apr 04, 2012 | not rated yet | 0
- Testing for mutations identified in squamous cell lung cancer tumors helps personalize treatment May 17, 2012 | not rated yet | 0
- EGFR gene signature predicts non-small cell lung cancer prognosis Jan 13, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
Marie Curie's leukemia
May 13, 2013 Does anyone know what might be the cause of Marie Curie's cancer
- More from Physics Forums - Medical Sciences
More news stories
The use of a smartphone application significantly improves patients' preparation for a colonoscopy, according to new research presented today at Digestive Disease Week (DDW). The preparation process, which begins days in ...
Cancer 5 hours ago | not rated yet | 0
Research presented at Digestive Disease Week (DDW) explores new methods for managing digestive health through diet and lifestyle.
Cancer 5 hours ago | not rated yet | 0
A ground-breaking advance in colonoscopy technology signals the future of colorectal care, according to research presented today at Digestive Disease Week(DDW). Additional research focuses on optimizing the minimal withdrawal ...
Cancer 20 hours ago | 5 / 5 (2) | 0
(HealthDay)—Concurrent use of two immune checkpoint antibodies—ipilimumab and nivolumab—may be effective for the treatment of advanced melanoma, according to a proof-of-principal study presented in ...
Cancer May 17, 2013 | not rated yet | 0
(HealthDay)—The risks of metastasis and death associated with cutaneous squamous cell carcinoma (CSCC) are low, but significant, and risk factors for poor outcome include tumor diameter, invasion beyond ...
Cancer May 17, 2013 | not rated yet | 0 |
Regular consumption of coffee is associated with a reduced risk of primary sclerosing cholangitis (PSC), an autoimmune liver disease, Mayo Clinic research shows. The findings were being presented at the Digestive Disease ...
6 hours ago | not rated yet | 0 |
Patients with treatment-resistant major depression saw dramatic improvement in their illness after treatment with ketamine, an anesthetic, according to the largest ketamine clinical trial to-date led by researchers from the ...
6 hours ago | 4.5 / 5 (2) | 0 |
There are significant cost and risk factors associated with two procedures commonly used to diagnose or treat gastrointestinal problems, according to research presented at Digestive Disease Week (DDW).
5 hours ago | not rated yet | 0
An increasing number of U.S. children are experiencing gastrointestinal issues that require interventions to resolve, according to research presented at Digestive Disease Week (DDW).
20 hours ago | not rated yet | 0 |
The latest makeover to a massive psychiatric tome honored by some, reviled by others and even called the "Bible" of mental disorders is being released Saturday with a host of new changes.
18 hours ago | not rated yet | 0
A new case of the deadly coronavirus has been detected in Saudi Arabia where 15 people have already died after contracting it, the health ministry announced on Saturday on its Internet website.
18 hours ago | not rated yet | 0