New target found for cancers resistant to Iressa and Herceptin
This image shows high-throughput fluorescence polarization maps of interactions with HER2 (above) and HER3 (below). Credit: Richard B. Jones
A more-sensitive method to analyze protein interactions has uncovered a new way that cancer cells may use the cell-surface molecule HER3 to drive tumor progression following treatment with HER1 and HER2 inhibitors.
The HER family of receptors has been linked to the development of a wide variety of human cancers. HER1 inhibitors such Iressa and HER2 inhibitors such as Herceptin are commonly used in the clinic for treatment of small cell lung carcinoma and breast cancer. A recent study suggests that HER3 levels can predict reduced breast cancer survival. However, HER3 inhibitors are not currently used in treatment.
Although the scientific basis for HER3's association with reduced patient survival was previously unclear, this study shows that HER3 could be up to 10 times more effective than HER2 in recruiting accessory proteins that drive the rapid proliferation, enhanced survival and distant spread of cancers.
The finding, published Sept. 4 in the journal PLOS ONE, came from one of the largest-ever quantitative analyses of binary-protein interactions to date. Researchers from the University of Chicago identified more than 1,000 new interactions for the four members of the HER family of growth-factor receptors, with the largest number of new additions linked to HER3.
"Our high-throughput system for measuring interactions between proteins found nearly 1,200 completely new interactions," said study author Richard B. Jones, PhD, assistant professor in the Ben May Department for Cancer Research and the Institute for Genomics and Systems Biology at the University of Chicago. "Most of them were comparatively weak interactions relative to those previously known, but they were still bona fide, tested and confirmed biochemical interactions."
HER2 has long been a poster child for translational research, a laboratory discovery that led to the drug Herceptin (trastuzumab), which worked wonders in clinical trials. Herceptin increased survival for women with aggressive breast cancers by 33 percent. An editorial in the New England Journal of Medicine described the results as "simply stunning … not evolutionary but revolutionary."
Amplification, or over-expression, of HER2 occurs in approximately 30 percent of breast cancer cases. It is associated with more aggressive disease, worse prognosis and increased recurrence. Although Herceptin typically extends life considerably, many patients eventually develop resistance to the drug, so alternative treatments are needed, and HER3 may represent a prime target.
"HER2 overexpression results from an obvious chromosomal aberration that is easily appreciated by standard clinical methods," Jones said. "HER3's role is less blatant. But the sheer volume of newly uncovered connections and the function of the proteins with which it connects lead us to believe that it is likely to be an important driver of cancer when its cousins, the EGFR or HER2, get shut down by existing clinical therapies."
"HER3 is better than even HER2 at recruiting the accessory players in cancer, such as SRC, and breast tumor kinase," he said. "When cancer grows resistant to treatments such as Herceptin, we believe that HER3 has the potential to assume the new disease-promoting role by actively working with other cancer promoting players that are not affected by the therapy."
This study, relying on newer research tools, builds substantially on a 2006 report by Jones and his former colleagues at Harvard University. They had modified recently developed gene array technology, now standard for genomics, to apply it to protein-omics—a new subclass of the field of proteomics that seeks to leverage the tools of systems biology to place massive protein data sets into biological context.
"That protein microarray method worked really well for identifying the strongest interactors of the HER receptors," Jones said, "but over time we became increasingly aware that we were missing the majority of potentially important protein-protein interactions due to their weaker affinity for the receptors."
So they developed a new method that is 10 to 50 times more sensitive. This enabled them to pick up many interactions that the older system missed because they were too weak or short lived.
Some biological interactions "stick like glue," Jones said. "They need to hold on to their neighbors to make things happen."
Others are more fleeting. A protein finds its target, holds on long enough to attach a chemical group, which activates the protein, then sends it on its way. These turned-on proteins "go to the nucleus or other parts of the cell where they deliver instructions," Jones said. "In cancer, those instructions might be to grow aberrantly and autonomously from their neighbors."
"HER2 mostly plays tackle," Jones said. "HER3 plays touch, but it can touch a lot of other players that may substantially contribute to tumor progression and metastasis."
The new technique, which Jones' team labeled "comprehensive binary interaction mapping via florescence polarization," is far more sensitive and specific than protein microarrays: 83 percent of the 1,405 unique biological interactions identified for the four members of the HER group were completely novel, and 100 previously suspected interactions were ruled out. The results could trigger drastic systems-level revisions of the understanding of the roles of these important proteins.
Despite considerable automation, the process was neither simple nor quick. "This study required about six years," Jones said. "First we had to express about 100 proteins from humans in the context of bacteria, purify them in the lab, and then expose them in solution to the nearly 100 unique potential interaction modules of each of the HER family proteins."
At that point, the robot, an automated cell-screening device at the University of Chicago Cell Screening Center known affectionately as Dot, stepped in. In a series of 12-hour robotic pipetting runs, Dot completed "about a half million pipetting events and measured the large matrix of interactions," Jones said.
Because the technique was new, the team was eager to verify the results. They divided the 1,200 protein-peptide connections into strong, medium and weak interactions and then tested the ability of other proteins with stronger interactions to displace the connection.
"Typically, in the field of biochemistry, more credence has been given to tight interactions, which are easier to identify and verify," Jones said. "However, the gold standard for authenticity of true and specific interactions is a competition assay. If a protein is really interacting, you should be able to compete it away from its partner by adding a competitive protein, like a baseball in the pocket of a glove would block another ball from entering. We were able to validate a representative subset of the interactions this way."
"Many protein interactions with known biological consequences exist that interact at affinities lower than those that we measured in this assay," he said. "This bolsters our confidence in the potential relevance of these interactions to biology. We are excited to now begin to test their relevance in cancer cells."
Journal reference: PLoS ONE
Provided by University of Chicago Medical Center
- Proteins do not predict outcome of herceptin treatment in HER2-positive breast cancer Dec 09, 2011 | not rated yet | 0
- Protein snapshots reveal clues to breast cancer outcomes May 05, 2011 | not rated yet | 0
- Hit multiple targets for maximum benefit in HER2-positive breast cancer, studies suggest Mar 08, 2011 | not rated yet | 0
- Class of breast cancer drugs could treat other types of cancer Nov 09, 2011 | not rated yet | 0
- New therapy for HER2-positive breast cancer developed Jul 26, 2011 | 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
How can there be villous adenoma in colon, if there are no villi there
18 hours ago As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
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...
- More from Physics Forums - Medical Sciences
More news stories
(HealthDay)—The American Cancer Society, which is celebrating on Wednesday a century of fighting a disease once viewed as a death sentence, is making a pledge to put itself out of business.
Cancer 7 hours ago | not rated yet | 0
National Lung Screening Trial (NLST) investigators also conclude that the 20 percent reduction in lung cancer mortality with low-dose computed tomography (LDCT) versus chest X-ray (CXR) screening previously reported in the ...
Cancer 8 hours ago | not rated yet | 0
Researchers have developed a new drug delivery system that allows inhalation of chemotherapeutic drugs to help treat lung cancer, and in laboratory and animal tests it appears to reduce the systemic damage ...
Cancer 11 hours ago | not rated yet | 0 |
When turned on, the gene p53 turns off cancer. However, when existing drugs boost p53, only a few tumors die – the rest resist the challenge. A study published in the journal Cell Reports shows how: tumors that live even i ...
Cancer 11 hours ago | not rated yet | 0 |
Study leader, Professor John Mathews from the University of Melbourne said this small increase in cancer risk must be weighed against the undoubted benefits from CT scans in diagnosing and monitoring disease.
Cancer 15 hours ago | not rated yet | 0
Existing research shows that bicyclists who wear helmets have an 88 percent lower risk of brain injury, but researchers at Boston Children's Hospital found that simply having bicycle helmet laws in place showed a 20 percent ...
1 hour ago | not rated yet | 0
Swiss scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young.
12 hours ago | 4.9 / 5 (7) | 0 |
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
12 hours ago | 4 / 5 (1) | 0 |
Until now, little was scientifically known about the human potential to cultivate compassion—the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.
9 hours ago | 5 / 5 (2) | 2 |
(HealthDay)—Migraines and depression can each cause a great deal of suffering, but new research indicates the combination of the two may be linked to something else entirely—a smaller brain.
8 hours ago | 4 / 5 (2) | 0 |
A new approach for immunizing against influenza elicited a more potent immune response and broader protection than the currently licensed seasonal influenza vaccines when tested in mice and ferrets. The vaccine ...
9 hours ago | not rated yet | 0 |