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."
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!
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
05.12.2016 | Earth Sciences
05.12.2016 | Physics and Astronomy
05.12.2016 | Life Sciences