Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Targeted cancer drugs may work by disrupting balance of cellular signals

14.11.2006
Study supports new model of drug action that may explain problems, suggest new approaches

Targeted cancer therapy drugs like Gleevec (imatinib) and Tarceva (erlotinib), which destroy tumors by interfering with specific proteins or protein pathways, may disrupt the balance between critical cellular signals in a way that leads to cell death.

In the November issue of Cancer Cell, researchers from the Massachusetts General Hospital Cancer Center present evidence for their theory, which runs counter to an alternative hypothesis called "oncogene addiction." Better understanding these drugs' mechanism of operation could help surmount current limitations on their usefulness and lead to the discovery of additional protein targets.

"It looks like these drugs reduce the activity of their target proteins in such a way that cell-death signals remain high while survival signals drop," says Jeffrey Settleman, PhD, director of the Center for Molecular Therapeutics at the MGH Cancer Center, senior author of the report. "This model gives us clues that could lead to more successful treatment strategies and answer questions about the limited effectiveness these drugs have had."

... more about:
»Cellular »EGFR »Kinase »Mutation »oncogene »survival

It has become apparent that certain forms of cancer depend on mutations in specific genes, called oncogenes, for their development and survival. These include the EGFR gene in non-small-cell lung cancer and a gene called BCR-ABL in leukemia. Both of those genes code for proteins called kinases, which regulate the processing of key cellular signals.

The cancer-associated mutations overactivate the kinases in ways that lead to the uncontrolled growth of a tumor.

Drugs that have been specifically designed to interfere with the activity of these kinases – Gleevec targets the BCR-ABL protein and both Tarceva and Iressa (gefitinib) inhibit EGFR activity – have been very successful in limited numbers of patients. But as yet researchers have not understood the molecular mechanism underlying these drugs' activity, information that might expand their usefulness to a broader patient population and address problems of resistance that can develop. The "oncogene addiction" theory proposes that the internal circuitry of tumor cells becomes so reliant on the oncogenic protein or the pathway it controls that the cells die if kinase activity is suppressed.

Since kinases controls two types of cellular signals – some leading to cellular survival, others to cell death – the MGH team proposed an alternative explanation: that survival signals drop quickly after kinase activity is suppress, releasing their control over persistant cell-death signals. To test this hypothesis, they conducted several experiments using oncogene-expressing cell lines. In lines expressing tumor-associated versions of BCR-ABL, EGFR, or another kinase called Src, the survival-associated signals dropped quickly after kinase activity was suppressed, while cell-death signals were maintained.

Because the oncogenes had been artificially introduced into those cell lines, the researchers then tested their model in human lung cancer cells with the EGFR mutation. Again, kinase suppression, this time by application of Iressa, produced a rapid reduction in survival signals and eventual cell death as cell-death signals rose. A subsequent experiment with the Src cell line showed that cells pushed into a malignant form by expression of the mutant kinase could survive after Src activity was suppressed if a survival signal was supplied from another source, implying that the cells are not totally dependent on the oncogene's activity.

"While all of these drugs have different targets, they appear to act in a similar way, causing a reduction in survival-promoting proteins while apoptotic [cell-death promoting] signals persist and drive the cells towards death," Settleman says. "We suggest that the term 'oncogenic shock' may be a more accurate way to describe a process in which the very thing that kept the tumor alive – overexpression of a kinase – is turned against itself when the balance is disrupted to allow the cell-death signals to predominate."

The new model also could explain why targeted drugs have not worked well in combination with standard chemotherapy drugs, which shut down the cell cycle and may actually halt the cell-death process, he adds. And if survival and apoptotic signals do drop and recover at different rates, giving these medications in a cyclic fashion, rather than continuously as currently prescribed, might better take advantage of the temporal windows of vulnerability and could possibly avoid drug resistance. Drugs that target the survival and cell death signals themselves may present another new strategy.

"These findings explain why activated kinases are such good targets and support the importance of searching for more," adds Settleman, a professor of Medicine at Harvard Medical School. "More than 500 kinases have been identified, but we only have a half-dozen targeted kinase inhibitors. Finding new treatment targets and identifying the patients whose tumors have those kinases may bring us closer to the goal of truly personalized cancer treatment."

Sue McGreevey | EurekAlert!
Further information:
http://www.mgh.harvard.edu/

Further reports about: Cellular EGFR Kinase Mutation oncogene survival

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>