When it comes to gene sequencing and personalized medicine for cancer, spotting an aberrant kinase is a home run. The proteins are relatively easy to target with drugs and plenty of kinase inhibitors already exist.
Now in a new study, University of Michigan Comprehensive Cancer Center researchers assess the complete landscape of a cancer's "kinome" expression and determine which kinases are acting up in a particular tumor. They go on to show that those particular kinases can be targeted with drugs – potentially combining multiple drugs to target multiple kinases.
"We have a small but effective inventory of 'druggable' mutations that we know play a role in cancer. As we are doing more sequencing, we're coming to realize just how small that inventory is. On the one hand, it's a limitation. On the other hand, there are numerous oncogenic kinases, and there are a lot of kinase inhibitors. Our goal is to determine how to match more of these therapies with the right patients," says senior study author Chandan Kumar-Sinha, Ph.D., research assistant professor at the Michigan Center for Translational Pathology.
The researchers looked at RNA sequencing data from 482 samples of both cancerous and non-cancerous tissue and identified the most highly expressed kinases in individual breast cancer and pancreatic cancer samples. They found certain common themes.
"A lot of samples showed one or two kinases that showed an outstandingly high 'outlier' expression," says Kumar-Sinha. It wasn't that the researchers always found a mutation – just that one or more kinases were expressed at a far higher level than all other kinases.
"We don't always know what's causing it to be overexpressed. But since it's there, we know that somehow the high expression of oncogenic kinases is advantageous to the cancer, and so we can therapeutically exploit that dependency," Kumar-Sinha says.
Results of the study appear online in the journal Cancer Discovery.
In breast cancer, the researchers spotted outlier expression of ERBB2 kinase in HER2-positive tumors, which would be expected. HER2-positive tumors can be treated with Herceptin. But they also found another kinase, called FGFR4 – and they found that adding a drug that blocks FGFR4, in combination with Herceptin, improved the anti-cancer effect. This was done only in cells in the laboratory, but the FGFR4-inhibitor continued to be effective in cells even after they became resistant to Herceptin.
In the pancreatic cancer samples, the researchers found several different kinases that have drugs that work against them, including MET, AKT and PLK. Pancreatic cancer is one of the most deadly types of cancer, often diagnosed in its late stages when treatments are not very effective. The main driver of pancreatic cancer, a mutation in a gene called KRAS, has proven difficult to target with treatments.
In the lab, researchers blocked the outlier kinases and found it had an effect against the cancer cells. They then blocked KRAS – something that can be done in the lab but has not been achieved in patients with pancreatic cancer – and found an even larger effect.
"If in the future we could target KRAS in patients and also hit the outlier kinases, it could have a huge impact on treatment of pancreatic cancer," Kumar-Sinha says.
These findings must still be tested in patients, but researchers are hopeful that targeting specific kinases expressed in an individual patient's tumor could make a difference.
The U-M Comprehensive Cancer Center is currently using gene sequencing techniques to help match advanced cancer patients with potential clinical trial opportunities based on the make-up of their tumor.
"We hope kinases will represent another available avenue with whole genome sequencing. If we can identify rational multiple targets for treatment, it's more effective. This gets us one of those targets," Kumar-Sinha says.
Additional authors: Vishal Kothari, Iris Wei, Sunita Shankar, Shanker Kalyana-Sundaram, Lidong Wang, Linda W. Ma, Pankaj Vats, Catherine S. Grasso, Dan R. Robinson, Yi-Mi Wu, Xuhong Cao, Diane M. Simeone, Arul M. Chinnaiyan, all from U-M
Funding: National Cancer Institute grants 5-R21-CA-155992-02, 2T32CA009672-21, R01CA131045-01, P50CA130810-1A; Department of Defense Era of Hope grant BC075023; Rich Rogel Fund for Pancreatic Cancer Research; Doris Duke Charitable Foundation; American Cancer Society; U-M's A. Alfred Taubman Research Institute; U-M GI SPORE
Reference: Cancer Discovery, "Outlier Kinase Expression by RNA Sequencing as Targets for Precision Therapy," published online Feb. 5, 2013, doi:10.1158/2159-8290.CD-12-0336Resources:
Nicole Fawcett | EurekAlert!
A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg
Urbanization to convert 300,000 km2 of prime croplands
27.12.2016 | Mercator Research Institute on Global Commons and Climate Change (MCC) gGmbH
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Trade Fair News
16.01.2017 | Automotive Engineering
16.01.2017 | Life Sciences